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Barbieux S, Jouenne F, Machet MC, Fraitag S, Macagno N, Battistella M, Cribier B, Sohier P, Laurent-Roussel S, Carlotti A, Beltzung F, Jullié ML, Moulonguet I, Basset-Seguin N, Deschamps L, Mourah S, Samimi M, Guyétant S, Kervarrec T. Re-evaluation of the concept of basaloid follicular hamartoma associated with naevoid basal cell carcinoma syndrome: a morphological, immunohistochemical and molecular study. Pathology 2025; 57:49-56. [PMID: 39455322 DOI: 10.1016/j.pathol.2024.06.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Revised: 06/06/2024] [Accepted: 06/23/2024] [Indexed: 10/28/2024]
Abstract
Naevoid basal cell carcinoma syndrome (NBCCS) is a rare genodermatosis caused by germline mutations in genes of the Sonic Hedgehog (SHH) pathway and is characterised by early onset of multiple basal cell carcinomas (BCCs). Although skin tumours with follicular differentiation, notably basaloid follicular hamartoma (BFH), have been reported in NBCCS, their relations with BCC are poorly defined. In this context, the aim of this study was to clarify morphological, immunohistochemical and molecular features of BFH arising in a context of NBCCS. A total of 140 skin tumours from NBCCS and 140 control BCC tumours were reviewed, blinded to clinical data and classified as BCC or BFH. The morphological characteristics of these two groups were then compared. Twenty cases were submitted for immunohistochemical and molecular analysis. Thirty-three tumours among the exploratory cohort were classified as BFH and were exclusively detected in NBCCS patients. Histopathological criteria that were significantly different from BCC were as follows: a small size (<1.5 mm), connection to a hair follicle, arborescent organoid architecture, lack of cytological atypia and infundibulocystic differentiation. Immunohistochemical analysis confirmed activation of the SHH pathway in these lesions. Targeted next-generation sequencing suggested that MYCN and GLI2/3 amplifications and TP53 mutations might be involved in progression of these follicular tumours to BCC. Our study confirms the high prevalence of BFH, representing up to 24% of skin tumours in NBCCS and potentially being BCC precursors.
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Affiliation(s)
- Simon Barbieux
- Department of Pathology, Université de Tours, Centre Hospitalier Universitaire de Tours, Tours, France; Platform of Somatic Tumor Molecular Genetics, Université de Tours, Centre Hospitalier Universitaire de Tours, Tours, France.
| | - Fanélie Jouenne
- Department of Tumors Genomics and Pharmacology, Hôpital Saint-Louis, AP-HP, Paris, France
| | - Marie-Christine Machet
- Department of Pathology, Université de Tours, Centre Hospitalier Universitaire de Tours, Tours, France
| | - Sylvie Fraitag
- Department of Pathology, Hôpital Necker-Enfants Malades, AP-HP, Paris, France
| | - Nicolas Macagno
- Department of Pathology, Centre Hospitalier de la Timone, Assistance Publique-Hôpitaux de Marseille, Marseille, France; CARADERM Network, France
| | - Maxime Battistella
- CARADERM Network, France; Department of Pathology, Hôpital Saint-Louis, AP-HP, Paris, France
| | - Bernard Cribier
- CARADERM Network, France; Department of Dermatology, Hôpitaux Universitaires et Université de Strasbourg, Strasbourg, France
| | - Pierre Sohier
- CARADERM Network, France; Department of Pathology, Hôpital Cochin, AP-HP, Centre-Université Paris Cité, Paris, France
| | - Sara Laurent-Roussel
- CARADERM Network, France; Department of Pathology, Hôpital Cochin, AP-HP, Centre-Université Paris Cité, Paris, France; National Center of Dermatopathology - La Roquette, Paris, France
| | - Agnès Carlotti
- Department of Pathology, Hôpital Cochin, AP-HP, Centre-Université Paris Cité, Paris, France
| | - Fanny Beltzung
- Department of Pathology, Hôpital Haut-Lévêque, CHU de Bordeaux, Pessac, France
| | - Marie-Laure Jullié
- CARADERM Network, France; Department of Pathology, Hôpital Haut-Lévêque, CHU de Bordeaux, Pessac, France
| | | | - Nicole Basset-Seguin
- CARADERM Network, France; Department of Dermatology, Hôpital Saint-Louis, AP-HP, Paris, France
| | - Lydia Deschamps
- CARADERM Network, France; Department of Pathology, Hôpital Bichat, AP-HP, Paris, France
| | - Samia Mourah
- Department of Tumors Genomics and Pharmacology, Hôpital Saint-Louis, AP-HP, Paris, France
| | - Mahtab Samimi
- CARADERM Network, France; Department of Dermatology, Université de Tours, Centre Hospitalier Universitaire de Tours, Tours, France; 'Biologie des infections à polyomavirus' Team, UMR INRA ISP 1282, Université de Tours, Tours, France
| | - Serge Guyétant
- Department of Pathology, Université de Tours, Centre Hospitalier Universitaire de Tours, Tours, France; Platform of Somatic Tumor Molecular Genetics, Université de Tours, Centre Hospitalier Universitaire de Tours, Tours, France; 'Biologie des infections à polyomavirus' Team, UMR INRA ISP 1282, Université de Tours, Tours, France
| | - Thibault Kervarrec
- Department of Pathology, Université de Tours, Centre Hospitalier Universitaire de Tours, Tours, France; CARADERM Network, France; 'Biologie des infections à polyomavirus' Team, UMR INRA ISP 1282, Université de Tours, Tours, France
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Shen AY, Seth I, Marcaccini G, Rozen WM, Ross RJ. Basal Cell Carcinoma Arising in a Previous Full-Thickness Graft Donor Site: A Case Report and Comprehensive Literature Review. J Clin Med 2025; 14:591. [PMID: 39860596 PMCID: PMC11766017 DOI: 10.3390/jcm14020591] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2024] [Revised: 01/12/2025] [Accepted: 01/14/2025] [Indexed: 01/27/2025] Open
Abstract
Background/Objectives: Basal cell carcinoma (BCC), the most common skin malignancy, typically occurs in sun-exposed areas but can develop in atypical locations, such as scars, burns, and skin graft donor sites. BCC arising specifically in full-thickness skin graft donor sites is exceptionally rare. This study presents a unique case of BCC occurring 16 years post-graft harvesting and provides a comprehensive literature review to analyze clinical patterns, possible etiopathogenesis, and treatment strategies. Methods: A case report was described and a comprehensive literature review was conducted using PubMed, Scopus, and Web of Science (up to November 2024). Studies were screened for cases of BCC involving skin graft donor and recipient sites. Extracted data included demographics, graft type, latency period, histopathology, treatment, and outcomes. Results: A 68-year-old woman presented with biopsy-confirmed mixed nodular and micronodular BCC at the donor site of a full-thickness skin graft 16 years after its use for nasal reconstruction. Surgical excision with clear margins resulted in complete resolution without recurrence. A literature analysis revealed seven cases of graft-associated BCC, predominantly affecting older females. Partial-thickness grafts were frequently involved, with latency periods ranging from 1 to 61 years. Nodular BCC was the most common histological subtype, and surgical excision remained the primary and most effective treatment. Conclusions: Although rare, BCC can develop in skin graft donor sites after prolonged latency. Chronic trauma, impaired vascularization, and genetic alterations likely contribute to tumorigenesis. Lifelong surveillance, early detection, and timely intervention are critical to improving outcomes.
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Affiliation(s)
- Amanda Y. Shen
- Department of Plastic and Reconstructive Surgery, Peninsula Health, Melbourne, VIC 3199, Australia; (A.Y.S.)
| | - Ishith Seth
- Department of Plastic and Reconstructive Surgery, Peninsula Health, Melbourne, VIC 3199, Australia; (A.Y.S.)
- Faculty of Medicine and Surgery, Monash University, Melbourne, VIC 3004, Australia
| | - Gianluca Marcaccini
- Department of Plastic and Reconstructive Surgery, Peninsula Health, Melbourne, VIC 3199, Australia; (A.Y.S.)
| | - Warren M. Rozen
- Department of Plastic and Reconstructive Surgery, Peninsula Health, Melbourne, VIC 3199, Australia; (A.Y.S.)
- Faculty of Medicine and Surgery, Monash University, Melbourne, VIC 3004, Australia
| | - Richard J. Ross
- Department of Plastic and Reconstructive Surgery, Peninsula Health, Melbourne, VIC 3199, Australia; (A.Y.S.)
- Faculty of Medicine and Surgery, Monash University, Melbourne, VIC 3004, Australia
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3
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Ambrosio L, Roberti V, Uribe P, Chello C, Villaseca M, Navarrete-Dechent C, Retrosi C, Conforti C, Pellacani G. Discovering basal cell carcinoma cellular origin via reflectance confocal microscopy. J Eur Acad Dermatol Venereol 2024. [PMID: 39699909 DOI: 10.1111/jdv.20507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Accepted: 12/09/2024] [Indexed: 12/20/2024]
Affiliation(s)
- Luca Ambrosio
- Dermatology Unit, Department of Clinical Internal Anesthesiologic Cardiovascular Sciences, "Sapienza" University of Rome, Rome, Italy
- IDI-IRCCS, Dermatological Research Hospital, Rome, Italy
| | - Vincenzo Roberti
- Dermatology Unit, Department of Clinical Internal Anesthesiologic Cardiovascular Sciences, "Sapienza" University of Rome, Rome, Italy
| | - Pablo Uribe
- Department of Dermatology, Escuela de Medicina, Pontificia Universidad Catolica de Chile, Santiago, Chile
| | - Camilla Chello
- Dermatology Unit, Department of Clinical Internal Anesthesiologic Cardiovascular Sciences, "Sapienza" University of Rome, Rome, Italy
| | - Miguel Villaseca
- Department of Dermatology, Escuela de Medicina, Pontificia Universidad Catolica de Chile, Santiago, Chile
| | - Cristian Navarrete-Dechent
- Department of Dermatology, Escuela de Medicina, Pontificia Universidad Catolica de Chile, Santiago, Chile
| | - Chiara Retrosi
- IDI-IRCCS, Dermatological Research Hospital, Rome, Italy
| | | | - Giovanni Pellacani
- Dermatology Unit, Department of Clinical Internal Anesthesiologic Cardiovascular Sciences, "Sapienza" University of Rome, Rome, Italy
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4
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Wang S, Sun J. An ulcerated plaque on the palm. Indian J Dermatol Venereol Leprol 2024; 0:1-3. [PMID: 39508654 DOI: 10.25259/ijdvl_1158_2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Accepted: 09/02/2024] [Indexed: 11/15/2024]
Affiliation(s)
- Shu Wang
- Department of Dermatology and Venereology, Peking University First Hospital, Xicheng District, Beijing, China
| | - Jingru Sun
- Department of Dermatology and Venereology, Peking University First Hospital, Xicheng District, Beijing, China
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5
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Cebolla-Verdugo M, Llamas-Segura C, Velasco-Amador JP, Almazán-Fernández FM, Ruiz-Villaverde R. Understanding and managing locally advanced basal cell carcinoma: insights into pathogenesis, therapeutic strategies, and the role of hedgehog pathway inhibitors. Ital J Dermatol Venerol 2024; 159:530-542. [PMID: 39422527 DOI: 10.23736/s2784-8671.24.07993-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2024]
Abstract
Understanding and managing locally advanced basal cell carcinoma (BCC) is crucial given its substantial prevalence and potential for local tissue destruction. While BCC typically exhibits low metastatic potential, its high incidence underscores the need for enhanced therapeutic strategies. Locally advanced BCC presents unique challenges, often necessitating aggressive interventions to prevent disfigurement and functional impairment. The emergence of hedgehog pathway inhibitors (HHIs) offers promising therapeutic avenues by targeting aberrant hedgehog signaling, a key driver in BCC pathogenesis. Thus, elucidating the pathogenesis of locally advanced BCC and exploring the role of HHIs are critical endeavors in effectively managing this prevalent carcinoma. Epidemiologically, BCC primarily affects individuals with fair skin and chronic sun exposure, with an increasing incidence noted among younger age groups. Risk factors include UV radiation exposure, familial history of skin cancer, immunosuppression, and genetic syndromes such as basal cell nevus syndrome and xeroderma pigmentosum. Pathogenetically, BCC arises from cells in the skin's epidermis, with hedgehog pathway activation being a primary genetic driver, involving mutations in PTCH1 and SMO. Resistance to hedgehog inhibitors may occur due to genetic changes, complicating treatment strategies. BCC is characterized by low immunogenicity, which hinders immune response and contributes to treatment challenges. Enhanced understanding of the epidemiology, risk factors, and pathogenesis of locally advanced BCC, along with the development of targeted therapeutic approaches such as hedgehog pathway inhibitors, is essential for effectively managing this prevalent carcinoma and improving patient outcomes.
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Affiliation(s)
- Marta Cebolla-Verdugo
- Department of Dermatology, San Cecilio University Hospital, Granada, Spain
- Instituto Biosanitario de Granada, Ibs, Granada, Spain
| | - Carlos Llamas-Segura
- Department of Dermatology, San Cecilio University Hospital, Granada, Spain
- Instituto Biosanitario de Granada, Ibs, Granada, Spain
| | - Juan P Velasco-Amador
- Department of Dermatology, San Cecilio University Hospital, Granada, Spain
- Instituto Biosanitario de Granada, Ibs, Granada, Spain
| | - Francisco M Almazán-Fernández
- Department of Dermatology, San Cecilio University Hospital, Granada, Spain
- Instituto Biosanitario de Granada, Ibs, Granada, Spain
| | - Ricardo Ruiz-Villaverde
- Department of Dermatology, San Cecilio University Hospital, Granada, Spain -
- Instituto Biosanitario de Granada, Ibs, Granada, Spain
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6
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Nicoletti G, Saler M, Moro U, Faga A. Dysembryogenetic Pathogenesis of Basal Cell Carcinoma: The Evidence to Date. Int J Mol Sci 2024; 25:8452. [PMID: 39126021 PMCID: PMC11312899 DOI: 10.3390/ijms25158452] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2024] [Revised: 07/28/2024] [Accepted: 07/29/2024] [Indexed: 08/12/2024] Open
Abstract
The Basal Cell Carcinoma (BCC) is a sort of unique tumour due to its combined peculiar histological features and clinical behaviour, such as the constant binary involvement of the epithelium and the stroma, the virtual absence of metastases and the predilection of specific anatomical sites for both onset and spread. A potential correlation between the onset of BCC and a dysembryogenetic process has long been hypothesised. A selective investigation of PubMed-indexed publications supporting this theory retrieved 64 selected articles published between 1901 and 2024. From our analysis of the literature review, five main research domains on the dysembryogenetic pathogenesis of BCC were identified: (1) The correlation between the topographic distribution of BCC and the macroscopic embryology, (2) the correlation between BCC and the microscopic embryology, (3) the genetic BCC, (4) the correlation between BCC and the hair follicle and (5) the correlation between BCC and the molecular embryology with a specific focus on the Hedgehog signalling pathway. A large amount of data from microscopic and molecular research consistently supports the hypothesis of a dysembryogenetic pathogenesis of BCC. Such evidence is promoting advances in the clinical management of this disease, with innovative targeted molecular therapies on an immune modulating basis being developed.
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Affiliation(s)
- Giovanni Nicoletti
- Plastic and Reconstructive Surgery, Department of Clinical Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Viale Camillo Golgi, 27100 Pavia, Italy;
- Advanced Technologies for Regenerative Medicine and Inductive Surgery Research Center, University of Pavia, Viale Brambilla, 74, 27100 Pavia, Italy;
- Surgery Unit, Azienda Socio-Sanitaria Territoriale di Pavia, Viale Repubblica, 34, 27100 Pavia, Italy
- Integrated Unit of Experimental Surgery, Advanced Microsurgery and Regenerative Medicine, University of Pavia, Via Adolfo Ferrata, 9, 27100 Pavia, Italy
| | - Marco Saler
- Plastic and Reconstructive Surgery, Department of Clinical Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Viale Camillo Golgi, 27100 Pavia, Italy;
- Advanced Technologies for Regenerative Medicine and Inductive Surgery Research Center, University of Pavia, Viale Brambilla, 74, 27100 Pavia, Italy;
- Integrated Unit of Experimental Surgery, Advanced Microsurgery and Regenerative Medicine, University of Pavia, Via Adolfo Ferrata, 9, 27100 Pavia, Italy
| | | | - Angela Faga
- Advanced Technologies for Regenerative Medicine and Inductive Surgery Research Center, University of Pavia, Viale Brambilla, 74, 27100 Pavia, Italy;
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7
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Dermitzakis I, Kampitsi DD, Manthou ME, Evangelidis P, Vakirlis E, Meditskou S, Theotokis P. Ontogeny of Skin Stem Cells and Molecular Underpinnings. Curr Issues Mol Biol 2024; 46:8118-8147. [PMID: 39194698 DOI: 10.3390/cimb46080481] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Revised: 07/21/2024] [Accepted: 07/25/2024] [Indexed: 08/29/2024] Open
Abstract
Skin stem cells (SCs) play a pivotal role in supporting tissue homeostasis. Several types of SCs are responsible for maintaining and regenerating skin tissue. These include bulge SCs and others residing in the interfollicular epidermis, infundibulum, isthmus, sebaceous glands, and sweat glands. The emergence of skin SCs commences during embryogenesis, where multipotent SCs arise from various precursor populations. These early events set the foundation for the diverse pool of SCs that will reside in the adult skin, ready to respond to tissue repair and regeneration demands. A network of molecular cues regulates skin SC behavior, balancing quiescence, self-renewal, and differentiation. The disruption of this delicate equilibrium can lead to SC exhaustion, impaired wound healing, and pathological conditions such as skin cancer. The present review explores the intricate mechanisms governing the development, activation, and differentiation of skin SCs, shedding light on the molecular signaling pathways that drive their fate decisions and skin homeostasis. Unraveling the complexities of these molecular drivers not only enhances our fundamental knowledge of skin biology but also holds promise for developing novel strategies to modulate skin SC fate for regenerative medicine applications, ultimately benefiting patients with skin disorders and injuries.
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Affiliation(s)
- Iasonas Dermitzakis
- Department of Histology-Embryology, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
| | - Despoina Dimitria Kampitsi
- Department of Histology-Embryology, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
| | - Maria Eleni Manthou
- Department of Histology-Embryology, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
| | - Paschalis Evangelidis
- Hematology Unit-Hemophilia Centre, 2nd Propedeutic Department of Internal Medicine, Hippocration Hospital, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece
| | - Efstratios Vakirlis
- First Department of Dermatology and Venereology, School of Medicine, Aristotle University of Thessaloniki, 54643 Thessaloniki, Greece
| | - Soultana Meditskou
- Department of Histology-Embryology, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
| | - Paschalis Theotokis
- Department of Histology-Embryology, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
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8
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Patel AS, Yanai I. A developmental constraint model of cancer cell states and tumor heterogeneity. Cell 2024; 187:2907-2918. [PMID: 38848676 PMCID: PMC11256907 DOI: 10.1016/j.cell.2024.04.032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Revised: 12/29/2023] [Accepted: 04/24/2024] [Indexed: 06/09/2024]
Abstract
Cancer is a disease that stems from a fundamental liability inherent to multicellular life forms in which an individual cell is capable of reneging on the interests of the collective organism. Although cancer is commonly described as an evolutionary process, a less appreciated aspect of tumorigenesis may be the constraints imposed by the organism's developmental programs. Recent work from single-cell transcriptomic analyses across a range of cancer types has revealed the recurrence, plasticity, and co-option of distinct cellular states among cancer cell populations. Here, we note that across diverse cancer types, the observed cell states are proximate within the developmental hierarchy of the cell of origin. We thus posit a model by which cancer cell states are directly constrained by the organism's "developmental map." According to this model, a population of cancer cells traverses the developmental map, thereby generating a heterogeneous set of states whose interactions underpin emergent tumor behavior.
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Affiliation(s)
- Ayushi S Patel
- Institute for Systems Genetics, NYU Grossman School of Medicine, New York, NY, USA; Department of Biochemistry & Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY, USA; Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA
| | - Itai Yanai
- Institute for Systems Genetics, NYU Grossman School of Medicine, New York, NY, USA; Department of Biochemistry & Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY, USA; Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA.
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9
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Liu YA, Aung PP, Wang Y, Ning J, Nagarajan P, Curry JL, Torres-Cabala CA, Ivan D, Prieto VG, Ding Q, Cho WC. TRPS1 expression in non-melanocytic cutaneous neoplasms: an immunohistochemical analysis of 200 cases. J Pathol Transl Med 2024; 58:72-80. [PMID: 38389280 PMCID: PMC10948250 DOI: 10.4132/jptm.2024.01.23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Revised: 01/09/2024] [Accepted: 01/18/2024] [Indexed: 02/24/2024] Open
Abstract
BACKGROUND Although trichorhinophalangeal syndrome type 1 (TRPS1) was initially thought to be highly sensitive and specific for carcinomas and mesenchymal tumors of mammary origin, more recent data suggest its expression is not limited to breast neoplasms but also can be seen in other cutaneous neoplasms, such as extramammary Paget disease and squamous cell carcinoma (SCC) in situ. METHODS Two-hundred cases of non-melanocytic cutaneous neoplasm, including basal cell carcinomas (BCCs) (n = 41), SCCs (n = 35), Merkel cell carcinomas (MCCs) (n = 25), and adnexal neoplasms (n = 99), were tested for TRPS1 expression using a monoclonal anti- TRPS1 rabbit anti-human antibody. RESULTS TRPS1 expression was present in almost all cases of SCC (94%), with a median H-score of 200, while it was either absent or only focally present in most BCCs (90%), with a median H-score of 5. The difference between BCCs and SCCs in H-score was significant (p < .001). All MCCs (100%) lacked TRPS1 expression. TRPS1 expression was frequently seen in most adnexal neoplasms, benign and malignant, in variable intensity and proportion but was consistently absent in apocrine carcinomas. All endocrine mucin-producing sweat gland carcinomas (EMPSGCs) (100%, 6/6) showed diffuse and strong TRPS1 immunoreactivity, with a median H-score of 300, which was significantly different (p < .001) than that of BCCs. CONCLUSIONS Our study shows that TRPS1 may be an effective discriminatory marker for BCCs and SCCs. It also has a role in distinguishing BCCs from EMPSGCs.
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Affiliation(s)
- Yi A. Liu
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Phyu P. Aung
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yunyi Wang
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jing Ning
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Priyadharsini Nagarajan
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jonathan L. Curry
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Carlos A. Torres-Cabala
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Doina Ivan
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Victor G. Prieto
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Qingqing Ding
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Woo Cheal Cho
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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10
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Torun MT, Yılmaz GT. Can the Safe Surgical Margin Be Narrowed in Early-Stage Facial Basal Cell Carcinoma? Adv Skin Wound Care 2024; 37:1-7. [PMID: 38241456 DOI: 10.1097/asw.0000000000000093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2024]
Abstract
OBJECTIVE To examine factors that affect the positive surgical margins of facial basal cell carcinoma (BCC) and investigate whether the surgical margin value can be narrowed in early-stage facial BCCs. METHODS Ninety-five patients were divided into the three groups based on prognosis: good (n = 48), mixed (n = 32), and poor (n = 15). The good prognosis group (group 1) included nodular and superficial subtypes; the mixed prognosis group (group 2) included nodular-infiltrative, nodular-micronodular, and nodular-sclerosing subtypes; and the poor prognosis group (group 3) included infiltrative and micronodular subtypes. RESULTS Groups 1 and 2 differed from each other significantly in terms of positive surgical margin (P = .002) and tumor thickness (P = .008), but group 3 did not (P = .851 and P = .804, respectively). With regard to surgical method (primary vs local flap repair), only tumor localization varied significantly (P < .001). CONCLUSIONS Groups differed significantly in terms of surgical margin positivity, the distance of the tumor to the surgical margin, and the tumor thickness. The intact surgical margin was 2 mm on average in this study, and the authors suggest that it may be possible to revise the surgical margin values recommended in the literature.
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Affiliation(s)
- Mümtaz Taner Torun
- In the Faculty of Medicine, Bandırma Onyedi Eylül University, Balıkesir, Bandırma, Turkey, Mümtaz Taner Torun, MD, is Associate Professor, Department of Ear Nose and Throat Diseases; and Gülden Taşova Yılmaz, MD, is Assistant Professor, Department of Pathology
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11
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Ganier C, Mazin P, Herrera-Oropeza G, Du-Harpur X, Blakeley M, Gabriel J, Predeus AV, Cakir B, Prete M, Harun N, Darrigrand JF, Haiser A, Wyles S, Shaw T, Teichmann SA, Haniffa M, Watt FM, Lynch MD. Multiscale spatial mapping of cell populations across anatomical sites in healthy human skin and basal cell carcinoma. Proc Natl Acad Sci U S A 2024; 121:e2313326120. [PMID: 38165934 PMCID: PMC10786309 DOI: 10.1073/pnas.2313326120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2023] [Accepted: 11/13/2023] [Indexed: 01/04/2024] Open
Abstract
Our understanding of how human skin cells differ according to anatomical site and tumour formation is limited. To address this, we have created a multiscale spatial atlas of healthy skin and basal cell carcinoma (BCC), incorporating in vivo optical coherence tomography, single-cell RNA sequencing, spatial global transcriptional profiling, and in situ sequencing. Computational spatial deconvolution and projection revealed the localisation of distinct cell populations to specific tissue contexts. Although cell populations were conserved between healthy anatomical sites and in BCC, mesenchymal cell populations including fibroblasts and pericytes retained signatures of developmental origin. Spatial profiling and in silico lineage tracing support a hair follicle origin for BCC and demonstrate that cancer-associated fibroblasts are an expansion of a POSTN+ subpopulation associated with hair follicles in healthy skin. RGS5+ pericytes are also expanded in BCC suggesting a role in vascular remodelling. We propose that the identity of mesenchymal cell populations is regulated by signals emanating from adjacent structures and that these signals are repurposed to promote the expansion of skin cancer stroma. The resource we have created is publicly available in an interactive format for the research community.
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Affiliation(s)
- Clarisse Ganier
- Centre for Gene Therapy and Regenerative Medicine, King’s College London, Guy’s Hospital, LondonSE1 9RT, United Kingdom
| | - Pavel Mazin
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, CambridgeCB10 1SA, United Kingdom
| | - Gabriel Herrera-Oropeza
- Centre for Developmental Neurobiology, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, LondonSE1 1UL, United Kingdom
| | - Xinyi Du-Harpur
- Centre for Gene Therapy and Regenerative Medicine, King’s College London, Guy’s Hospital, LondonSE1 9RT, United Kingdom
- The Francis Crick Institute, LondonNW1 1AT, United Kingdom
| | - Matthew Blakeley
- Centre for Gene Therapy and Regenerative Medicine, King’s College London, Guy’s Hospital, LondonSE1 9RT, United Kingdom
| | - Jeyrroy Gabriel
- Centre for Gene Therapy and Regenerative Medicine, King’s College London, Guy’s Hospital, LondonSE1 9RT, United Kingdom
| | - Alexander V. Predeus
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, CambridgeCB10 1SA, United Kingdom
| | - Batuhan Cakir
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, CambridgeCB10 1SA, United Kingdom
| | - Martin Prete
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, CambridgeCB10 1SA, United Kingdom
| | - Nasrat Harun
- Centre for Gene Therapy and Regenerative Medicine, King’s College London, Guy’s Hospital, LondonSE1 9RT, United Kingdom
| | - Jean-Francois Darrigrand
- Centre for Gene Therapy and Regenerative Medicine, King’s College London, Guy’s Hospital, LondonSE1 9RT, United Kingdom
| | - Alexander Haiser
- Centre for Gene Therapy and Regenerative Medicine, King’s College London, Guy’s Hospital, LondonSE1 9RT, United Kingdom
| | - Saranya Wyles
- Department of Dermatology, Mayo Clinic, Rochester, MN55905
| | - Tanya Shaw
- Centre for Inflammation Biology and Cancer Immunology, King’s College London, LondonSE1 1UL, United Kingdom
| | - Sarah A. Teichmann
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, CambridgeCB10 1SA, United Kingdom
- Theory of Condensed Matter Group, Cavendish Laboratory, University of Cambridge, CambridgeCB3 0HE, United Kingdom
| | - Muzlifah Haniffa
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, CambridgeCB10 1SA, United Kingdom
- Biosciences Institute, Newcastle University, Newcastle upon TyneNE2 4HH, United Kingdom
- National Institute for Health Research Newcastle Biomedical Research Centre, Newcastle Hospitals National Health Service Foundation Trust, Newcastle upon TyneNE1 4LP, United Kingdom
| | - Fiona M. Watt
- Centre for Gene Therapy and Regenerative Medicine, King’s College London, Guy’s Hospital, LondonSE1 9RT, United Kingdom
- Directors’ Unit, European Molecular Biology Laboratory, Heidelberg69117, Germany
| | - Magnus D. Lynch
- Centre for Gene Therapy and Regenerative Medicine, King’s College London, Guy’s Hospital, LondonSE1 9RT, United Kingdom
- St. John’s Institute of Dermatology, King’s College London, Guy’s Hospital, LondonSE1 9RT, United Kingdom
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12
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Cao J, Zhang Z, Zhou L, Luo M, Li L, Li B, Nice EC, He W, Zheng S, Huang C. Oncofetal reprogramming in tumor development and progression: novel insights into cancer therapy. MedComm (Beijing) 2023; 4:e427. [PMID: 38045829 PMCID: PMC10693315 DOI: 10.1002/mco2.427] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 10/20/2023] [Accepted: 10/23/2023] [Indexed: 12/05/2023] Open
Abstract
Emerging evidence indicates that cancer cells can mimic characteristics of embryonic development, promoting their development and progression. Cancer cells share features with embryonic development, characterized by robust proliferation and differentiation regulated by signaling pathways such as Wnt, Notch, hedgehog, and Hippo signaling. In certain phase, these cells also mimic embryonic diapause and fertilized egg implantation to evade treatments or immune elimination and promote metastasis. Additionally, the upregulation of ATP-binding cassette (ABC) transporters, including multidrug resistance protein 1 (MDR1), multidrug resistance-associated protein 1 (MRP1), and breast cancer-resistant protein (BCRP), in drug-resistant cancer cells, analogous to their role in placental development, may facilitate chemotherapy efflux, further resulting in treatment resistance. In this review, we concentrate on the underlying mechanisms that contribute to tumor development and progression from the perspective of embryonic development, encompassing the dysregulation of developmental signaling pathways, the emergence of dormant cancer cells, immune microenvironment remodeling, and the hyperactivation of ABC transporters. Furthermore, we synthesize and emphasize the connections between cancer hallmarks and embryonic development, offering novel insights for the development of innovative cancer treatment strategies.
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Affiliation(s)
- Jiangjun Cao
- West China School of Basic Medical Sciences and Forensic Medicine, and Department of Biotherapy Cancer Center and State Key Laboratory of Biotherapy, West China HospitalSichuan UniversityChengduChina
| | - Zhe Zhang
- Zhejiang Provincial Key Laboratory of Pancreatic Diseasethe First Affiliated HospitalSchool of MedicineZhejiang UniversityZhejiangChina
| | - Li Zhou
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education)Department of Infectious Diseasesthe Second Affiliated HospitalInstitute for Viral Hepatitis, Chongqing Medical UniversityChongqingChina
| | - Maochao Luo
- West China School of Basic Medical Sciences and Forensic Medicine, and Department of Biotherapy Cancer Center and State Key Laboratory of Biotherapy, West China HospitalSichuan UniversityChengduChina
| | - Lei Li
- Department of anorectal surgeryHospital of Chengdu University of Traditional Chinese Medicine and Chengdu University of Traditional Chinese MedicineChengduChina
| | - Bowen Li
- West China School of Basic Medical Sciences and Forensic Medicine, and Department of Biotherapy Cancer Center and State Key Laboratory of Biotherapy, West China HospitalSichuan UniversityChengduChina
| | - Edouard C. Nice
- Department of Biochemistry and Molecular BiologyMonash UniversityClaytonVICAustralia
| | - Weifeng He
- State Key Laboratory of TraumaBurn and Combined InjuryInstitute of Burn Research, Southwest Hospital, Third Military Medical University (Army Medical University)ChongqingChina
| | - Shaojiang Zheng
- Hainan Cancer Medical Center of The First Affiliated Hospital, the Hainan Branch of National Clinical Research Center for Cancer, Hainan Engineering Research Center for Biological Sample Resources of Major DiseasesHainan Medical UniversityHaikouChina
- Key Laboratory of Tropical Cardiovascular Diseases Research of Hainan Province, Hainan Women and Children's Medical Center, Key Laboratory of Emergency and Trauma of Ministry of EducationHainan Medical UniversityHaikouChina
| | - Canhua Huang
- West China School of Basic Medical Sciences and Forensic Medicine, and Department of Biotherapy Cancer Center and State Key Laboratory of Biotherapy, West China HospitalSichuan UniversityChengduChina
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13
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Hekmatirad S, Moloudizargari M, Fallah M, Rahimi A, Poortahmasebi V, Asghari MH. Cancer-associated immune cells and their modulation by melatonin. Immunopharmacol Immunotoxicol 2023; 45:788-801. [PMID: 37489565 DOI: 10.1080/08923973.2023.2239489] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Accepted: 07/17/2023] [Indexed: 07/26/2023]
Abstract
OBJECTIVES Rapidly growing evidence suggests that immune cells play a key role in determining tumor progression. Tumor cells are surrounded by a microenvironment composed of different cell populations including immune cells. The cross talk between tumor cells and the neighboring microenvironment is an important factor to take into account while designing tumor therapies. Despite significant advances in immunotherapy strategies, a relatively small proportion of patients have successfully responded to them. Therefore, the search for safe and efficient drugs, which could be used alongside conventional therapies to boost the immune system against tumors, is an ongoing need. In the present work, the modulatory effects of melatonin on different components of tumor immune microenvironment are reviewed. METHODS A thorough literature review was performed in PubMed, Scopus, and Web of Science databases. All published papers in English on tumor immune microenvironment and the relevant modulatory effects of melatonin were scrutinized. RESULTS Melatonin modulates macrophage polarization and prevents M2 induction. Moreover, it prevents the conversion of fibroblasts into cancer-associated fibroblasts (CAFs) and prevents cancer cell stemness. In addition, it can affect the payload composition of tumor-derived exosomes (TEXs) and their secretion levels to favor a more effective anti-tumor immune response. Melatonin is a safe molecule that affects almost all components of the tumor immune microenvironment and prevents them from being negatively affected by the tumor. CONCLUSION Based on the effects of melatonin on normal cells, tumor cells and microenvironment components, it could be an efficient compound to be used in combination with conventional immune-targeted therapies to increase their efficacy.
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Affiliation(s)
- Shirin Hekmatirad
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Marjan Fallah
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Medicinal Plant Research Centre, Islamic Azad University, Amol, Iran
| | - Atena Rahimi
- Department of Pharmacology and Toxicology, School of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Vahdat Poortahmasebi
- Department of Bacteriology and Virology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Hossein Asghari
- Department of Pharmacology and Toxicology, School of Medicine, Babol University of Medical Sciences, Babol, Iran
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14
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CHAMBERS JK, ITO S, UCHIDA K. Feline papillomavirus-associated Merkel cell carcinoma: a comparative review with human Merkel cell carcinoma. J Vet Med Sci 2023; 85:1195-1209. [PMID: 37743525 PMCID: PMC10686778 DOI: 10.1292/jvms.23-0322] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Accepted: 08/28/2023] [Indexed: 09/26/2023] Open
Abstract
Merkel cell carcinoma (MCC) is a rare skin tumor that shares a similar immunophenotype with Merkel cells, although its origin is debatable. More than 80% of human MCC cases are associated with Merkel cell polyomavirus infections and viral gene integration. Recent studies have shown that the clinical and pathological characteristics of feline MCC are comparable to those of human MCC, including its occurrence in aged individuals, aggressive behavior, histopathological findings, and the expression of Merkel cell markers. More than 90% of feline MCC are positive for the Felis catus papillomavirus type 2 (FcaPV2) gene. Molecular changes involved in papillomavirus-associated tumorigenesis, such as increased p16 and decreased retinoblastoma (Rb) and p53 protein levels, were observed in FcaPV2-positive MCC, but not in FcaPV2-negative MCC cases. These features were also confirmed in FcaPV2-positive and -negative MCC cell lines. The expression of papillomavirus E6 and E7 genes, responsible for p53 degradation and Rb inhibition, respectively, was detected in tumor cells by in situ hybridization. Whole genome sequencing revealed the integration of FcaPV2 DNA into the host feline genome. MCC cases often develop concurrent skin lesions, such as viral plaque and squamous cell carcinoma, which are also associated with papillomavirus infection. These findings suggest that FcaPV2 infection and integration of viral genes are involved in the development of MCC in cats. This review provides an overview of the comparative pathology of feline and human MCC caused by different viruses and discusses their cell of origin.
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Affiliation(s)
- James K CHAMBERS
- Laboratory of Veterinary Pathology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Soma ITO
- Laboratory of Veterinary Pathology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Kazuyuki UCHIDA
- Laboratory of Veterinary Pathology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
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15
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Berl A, Shir-az O, Genish I, Biran H, Mann D, Singh A, Wise J, Kravtsov V, Kidron D, Golberg A, Vitkin E, Yakhini Z, Shalom A. Exploring multisite heterogeneity of human basal cell carcinoma proteome and transcriptome. PLoS One 2023; 18:e0293744. [PMID: 37948379 PMCID: PMC10637653 DOI: 10.1371/journal.pone.0293744] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Accepted: 10/18/2023] [Indexed: 11/12/2023] Open
Abstract
Basal cell carcinoma (BCC) is the most common type of skin cancer. Due to multiple, potential underlying molecular tumor aberrations, clinical treatment protocols are not well-defined. This study presents multisite molecular heterogeneity profiles of human BCC based on RNA and proteome profiling. Three areas from lesions excised from 9 patients were analyzed. The focus was gene expression profiles based on proteome and RNA measurements of intra-tumor heterogeneity from the same patient and inter-tumor heterogeneity in nodular, infiltrative, and superficial BCC tumor subtypes from different patients. We observed significant overlap in intra- and inter-tumor variability of proteome and RNA expression profiles, showing significant multisite heterogeneity of protein expression in the BCC tumors. Inter-subtype analysis has also identified unique proteins for each BCC subtype. This profiling leads to a deeper understanding of BCC molecular heterogeneity and potentially contributes to developing new sampling tools for personalized diagnostics therapeutic approaches to BCC.
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Affiliation(s)
- Ariel Berl
- Department of Plastic Surgery, Meir Medical Center, Kfar Sava, Israel, Affiliated with the Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Ofir Shir-az
- Department of Plastic Surgery, Meir Medical Center, Kfar Sava, Israel, Affiliated with the Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Ilai Genish
- Efi Arazi School of Computer Science, Reichman University, Herzliya, Israel
| | - Hadas Biran
- Department of Computer Science, Technion - Israel Institute of Technology, Haifa, Israel
| | - Din Mann
- Department of Plastic Surgery, Meir Medical Center, Kfar Sava, Israel, Affiliated with the Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Amrita Singh
- Department of Environmental Studies, Porter School of Environment and Earth Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Julia Wise
- Department of Environmental Studies, Porter School of Environment and Earth Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Vladimir Kravtsov
- Department of Pathology, Meir Medical Center, Kfar Sava, Israel, Affiliated with the Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Debora Kidron
- Department of Pathology, Meir Medical Center, Kfar Sava, Israel, Affiliated with the Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Alexander Golberg
- Department of Environmental Studies, Porter School of Environment and Earth Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Edward Vitkin
- Efi Arazi School of Computer Science, Reichman University, Herzliya, Israel
| | - Zohar Yakhini
- Efi Arazi School of Computer Science, Reichman University, Herzliya, Israel
- Department of Computer Science, Technion - Israel Institute of Technology, Haifa, Israel
| | - Avshalom Shalom
- Department of Plastic Surgery, Meir Medical Center, Kfar Sava, Israel, Affiliated with the Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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16
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Bansaccal N, Vieugue P, Sarate R, Song Y, Minguijon E, Miroshnikova YA, Zeuschner D, Collin A, Allard J, Engelman D, Delaunois AL, Liagre M, de Groote L, Timmerman E, Van Haver D, Impens F, Salmon I, Wickström SA, Sifrim A, Blanpain C. The extracellular matrix dictates regional competence for tumour initiation. Nature 2023; 623:828-835. [PMID: 37968399 PMCID: PMC7615367 DOI: 10.1038/s41586-023-06740-y] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Accepted: 10/11/2023] [Indexed: 11/17/2023]
Abstract
The skin epidermis is constantly renewed throughout life1,2. Disruption of the balance between renewal and differentiation can lead to uncontrolled growth and tumour initiation3. However, the ways in which oncogenic mutations affect the balance between renewal and differentiation and lead to clonal expansion, cell competition, tissue colonization and tumour development are unknown. Here, through multidisciplinary approaches that combine in vivo clonal analysis using intravital microscopy, single-cell analysis and functional analysis, we show how SmoM2-a constitutively active oncogenic mutant version of Smoothened (SMO) that induces the development of basal cell carcinoma-affects clonal competition and tumour initiation in real time. We found that expressing SmoM2 in the ear epidermis of mice induced clonal expansion together with tumour initiation and invasion. By contrast, expressing SmoM2 in the back-skin epidermis led to a clonal expansion that induced lateral cell competition without dermal invasion and tumour formation. Single-cell analysis showed that oncogene expression was associated with a cellular reprogramming of adult interfollicular cells into an embryonic hair follicle progenitor (EHFP) state in the ear but not in the back skin. Comparisons between the ear and the back skin revealed that the dermis has a very different composition in these two skin types, with increased stiffness and a denser collagen I network in the back skin. Decreasing the expression of collagen I in the back skin through treatment with collagenase, chronic UV exposure or natural ageing overcame the natural resistance of back-skin basal cells to undergoing EHFP reprogramming and tumour initiation after SmoM2 expression. Altogether, our study shows that the composition of the extracellular matrix regulates how susceptible different regions of the body are to tumour initiation and invasion.
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Affiliation(s)
- Nordin Bansaccal
- Laboratory of Stem Cells and Cancer, Université Libre de Bruxelles, Brussels, Belgium
| | - Pauline Vieugue
- Laboratory of Stem Cells and Cancer, Université Libre de Bruxelles, Brussels, Belgium
| | - Rahul Sarate
- Laboratory of Stem Cells and Cancer, Université Libre de Bruxelles, Brussels, Belgium
| | - Yura Song
- Laboratory of Stem Cells and Cancer, Université Libre de Bruxelles, Brussels, Belgium
| | - Esmeralda Minguijon
- Department of Pathology, CUB Hôpital Erasme, Hôpital Universitaire de Bruxelles, Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Yekaterina A Miroshnikova
- Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
- Max Planck Institute for Molecular Biomedicine, Münster, Germany
| | - Dagmar Zeuschner
- Max Planck Institute for Molecular Biomedicine, Münster, Germany
| | - Amandine Collin
- DIAPath, Center for Microscopy and Molecular Imaging (CMMI), Université Libre de Bruxelles (ULB), Gosselies, Belgium
| | - Justine Allard
- DIAPath, Center for Microscopy and Molecular Imaging (CMMI), Université Libre de Bruxelles (ULB), Gosselies, Belgium
| | - Dan Engelman
- Laboratory of Stem Cells and Cancer, Université Libre de Bruxelles, Brussels, Belgium
| | - Anne-Lise Delaunois
- Laboratory of Stem Cells and Cancer, Université Libre de Bruxelles, Brussels, Belgium
| | - Mélanie Liagre
- Laboratory of Stem Cells and Cancer, Université Libre de Bruxelles, Brussels, Belgium
| | - Leona de Groote
- Laboratory of Stem Cells and Cancer, Université Libre de Bruxelles, Brussels, Belgium
| | - Evy Timmerman
- VIB Center for Medical Biotechnology, VIB Proteomics Core, Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
| | - Delphi Van Haver
- VIB Center for Medical Biotechnology, VIB Proteomics Core, Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
| | - Francis Impens
- VIB Center for Medical Biotechnology, VIB Proteomics Core, Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
| | - Isabelle Salmon
- Department of Pathology, CUB Hôpital Erasme, Hôpital Universitaire de Bruxelles, Université Libre de Bruxelles (ULB), Brussels, Belgium
- DIAPath, Center for Microscopy and Molecular Imaging (CMMI), Université Libre de Bruxelles (ULB), Gosselies, Belgium
| | - Sara A Wickström
- Max Planck Institute for Molecular Biomedicine, Münster, Germany
- Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | | | - Cédric Blanpain
- Laboratory of Stem Cells and Cancer, Université Libre de Bruxelles, Brussels, Belgium.
- WELBIO, Université Libre de Bruxelles (ULB), Brussels, Belgium.
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17
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Vallini G, Calabrese L, Canino C, Trovato E, Gentileschi S, Rubegni P, Tognetti L. Signaling Pathways and Therapeutic Strategies in Advanced Basal Cell Carcinoma. Cells 2023; 12:2534. [PMID: 37947611 PMCID: PMC10647618 DOI: 10.3390/cells12212534] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Revised: 10/24/2023] [Accepted: 10/25/2023] [Indexed: 11/12/2023] Open
Abstract
Non-melanoma skin cancers (NMSCs) are the most common human neoplasms world-wide. In detail, basal cell carcinoma (BCC) is the most frequent malignancy in the fair-skinned population. The incidence of BCC remains difficult to assess due to the poor registration practice; however, it has been increasing in the last few years. Approximately, 85% of sporadic BCCs carry mutations in Hedgehog pathway genes, especially in PTCH, SUFU and SMO genes, which lead to the aberrant activation of GLI transcriptional factors, typically silent in cells of adult individuals. The management of advanced BCC (aBCC), both metastatic (mBCC) and locally advanced BCC (laBCC), not candidates for surgical excision or radiotherapy, remains challenging. The discovery of mutations in the Hh signaling pathway has paved the way for the development of Hh pathway inhibiting agents, such as vismodegib and sonidegib, which have represented a breakthrough in the aBCC management. However, the use of these agents is limited by the frequent occurrence of adverse events or the development of drug resistance. In this review, we thoroughly describe the current knowledge regarding the available options for the pharmacological management of aBCCs and provide a forward-looking update on novel therapeutic strategies that could enrich the therapeutic armamentarium of BCC in the near future.
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Affiliation(s)
- Giulia Vallini
- Department of Medical Biotechnologies, University of Siena, 53100 Siena, Italy
| | - Laura Calabrese
- Department of Medical, Surgical and Neurological Sciences, Division of Dermatology, University of Siena, 53100 Siena, Italy; (L.C.); (E.T.); (P.R.); (L.T.)
- Institute of Dermatology, Catholic University of the Sacred Heart, 00168 Rome, Italy
| | - Costanza Canino
- Department of Haematology, Oncology and Cell and Gene Therapy, IRCCS Bambino Gesù Children’s Hospital, 00165 Rome, Italy;
| | - Emanuele Trovato
- Department of Medical, Surgical and Neurological Sciences, Division of Dermatology, University of Siena, 53100 Siena, Italy; (L.C.); (E.T.); (P.R.); (L.T.)
| | - Stefano Gentileschi
- Department of Medical, Surgical and Neurological Sciences, Division of Rheumatology, University of Siena, 53100 Siena, Italy;
| | - Pietro Rubegni
- Department of Medical, Surgical and Neurological Sciences, Division of Dermatology, University of Siena, 53100 Siena, Italy; (L.C.); (E.T.); (P.R.); (L.T.)
| | - Linda Tognetti
- Department of Medical, Surgical and Neurological Sciences, Division of Dermatology, University of Siena, 53100 Siena, Italy; (L.C.); (E.T.); (P.R.); (L.T.)
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18
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Tietze JK, Heuschkel M, Krönert MIC, Kurth J, Bandow G, Ojak G, Grünwald P, Herold JI, Thiem A, Dreßler M, Krause BJ, Emmert S, Schwarzenböck SM. Topical 188Re Ionizing Radiation Therapy Exerts High Efficacy in Curing Nonmelanoma Skin Cancer. Clin Nucl Med 2023; 48:869-876. [PMID: 37682602 DOI: 10.1097/rlu.0000000000004824] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/09/2023]
Abstract
PURPOSE OF THE REPORT Nonmelanoma skin cancer (NMSC) is the most frequent malignancy. Surgical intervention is the common treatment but may lead to disappointing results; alternative treatment options are needed. METHODS In this monocentric pilot study, topical 188Re resin was investigated as a treatment for invasive NMSC up to 3-mm thickness. Twenty-two patients with 40 histologically confirmed NMSCs with a median size of 1.25 cm2 (range, 0.04-16.8 cm2) and a median tumor thickness of 0.35 mm (range, 0.1-2.1 mm) were included. Patients were treated once with 188Re resin with a targeted dose of 50 Gy. The median applied activity was 111.4 MBq (range, 21.0-168.0 MBq), and the median treatment time was 89 minutes (range, 38-175 minutes). The response rate, adverse events, and cosmetic outcome were assessed at 14 days, 4 months, and 12 months. RESULTS Response rate at 12 months was 97.5%, with 95% complete responses (clinically or histologically proven in case of clinical doubt). Most adverse events were reported at 14 days, with 20% itching and 12.5% mostly minor pain. Forty-nine percent of the lesions showed hypopigmentation only at 12 months. Forty-one percent of the lesions were graded as cosmetically superior to the expected result after surgery and 51.3% as comparable to successful surgery. The cosmetic outcome on the head and face was superior compared with the trunk and leg (P = 0.003). CONCLUSION 188Re resin is a highly effective treatment for NMSC up to 3-mm thickness and a valid alternative to surgery, specifically for tumors located on sensitive areas such as nose or ear.
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Affiliation(s)
- Julia K Tietze
- From the Clinic and Policlinic for Dermatology and Venereology
| | - Martin Heuschkel
- Department of Nuclear Medicine, University Medical Center Rostock, Rostock, Germany
| | | | - Jens Kurth
- Department of Nuclear Medicine, University Medical Center Rostock, Rostock, Germany
| | - Gesine Bandow
- From the Clinic and Policlinic for Dermatology and Venereology
| | - Gregor Ojak
- From the Clinic and Policlinic for Dermatology and Venereology
| | - Pavel Grünwald
- From the Clinic and Policlinic for Dermatology and Venereology
| | | | - Alexander Thiem
- From the Clinic and Policlinic for Dermatology and Venereology
| | - Miriam Dreßler
- From the Clinic and Policlinic for Dermatology and Venereology
| | - Bernd J Krause
- Department of Nuclear Medicine, University Medical Center Rostock, Rostock, Germany
| | - Steffen Emmert
- From the Clinic and Policlinic for Dermatology and Venereology
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19
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Peris K, Fargnoli MC, Kaufmann R, Arenberger P, Bastholt L, Seguin NB, Bataille V, Brochez L, Del Marmol V, Dummer R, Forsea AM, Gaudy-Marqueste C, Harwood CA, Hauschild A, Höller C, Kandolf L, Kellerners-Smeets NWJ, Lallas A, Leiter U, Malvehy J, Marinović B, Mijuskovic Z, Moreno-Ramirez D, Nagore E, Nathan P, Stratigos AJ, Stockfleth E, Tagliaferri L, Trakatelli M, Vieira R, Zalaudek I, Garbe C. European consensus-based interdisciplinary guideline for diagnosis and treatment of basal cell carcinoma-update 2023. Eur J Cancer 2023; 192:113254. [PMID: 37604067 DOI: 10.1016/j.ejca.2023.113254] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Accepted: 07/18/2023] [Indexed: 08/23/2023]
Abstract
Basal cell carcinoma (BCC) is the most common malignant tumour in white populations. Multidisciplinary experts from European Association of Dermato-Oncology (EADO), European Dermatology Forum, European Society for Radiotherapy and Oncology (ESTRO), Union Européenne des Médecins Spécialistes, and the European Academy of Dermatology and Venereology developed updated recommendations on diagnosis and treatment of BCC. BCCs were categorised into 'easy-to-treat' (common) and 'difficult-to-treat' according to the new EADO clinical classification. Diagnosis is based on clinico-dermatoscopic features, although histopathological confirmation is mandatory in equivocal lesions. The first-line treatment of BCC is complete surgery. Micrographically controlled surgery shall be offered in high-risk and recurrent BCC, and BCC located on critical anatomical sites. Topical therapies and destructive approaches can be considered in patients with low-risk superficial BCC. Photodynamic therapy is an effective treatment for superficial and low-risk nodular BCCs. Management of 'difficult-to-treat' BCCs should be discussed by a multidisciplinary tumour board. Hedgehog inhibitors (HHIs), vismodegib or sonidegib, should be offered to patients with locally advanced and metastatic BCC. Immunotherapy with anti-PD1 antibodies (cemiplimab) is a second-line treatment in patients with a progression of disease, contraindication, or intolerance to HHI therapy. Radiotherapy represents a valid alternative in patients who are not candidates for or decline surgery, especially elderly patients. Electrochemotherapy may be offered when surgery or radiotherapy is contraindicated. In Gorlin patients, regular skin examinations are required to diagnose and treat BCCs at an early stage. Long-term follow-up is recommended in patients with high-risk BCC, multiple BCCs, and Gorlin syndrome.
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Affiliation(s)
- Ketty Peris
- Institute of Dermatology, Catholic University of the Sacred Heart, Rome, Italy; Fondazione Policlinico Universitario A. Gemelli, IRCCS, Rome, Italy.
| | - Maria Concetta Fargnoli
- Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
| | - Roland Kaufmann
- Department of Dermatology, Venereology and Allergology, University Hospital Frankfurt, Germany
| | - Petr Arenberger
- Department of Dermatovenereology, Third Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Lars Bastholt
- Department of Oncology, Odense University Hospital, Denmark
| | | | - Veronique Bataille
- Twin Research and Genetic Epidemiology Unit, School of Basic & Medical Biosciences, King's College London, London SE1 7EH, UK
| | - Lieve Brochez
- Department of Dermatology, University Hospital Ghent, Ghent, Belgium
| | - Veronique Del Marmol
- Department of Dermatology, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium
| | - Reinhard Dummer
- Department of Dermatology, University Hospital Zurich and University Zurich, Switzerland
| | - Ana-Marie Forsea
- Department of Oncologic Dermatology, Elias University Hospital Bucharest, Carol Davila University of Medicine and Pharmacy Bucharest, Bucharest, Romania
| | | | - Catherine A Harwood
- Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Axel Hauschild
- Department of Dermatology, University of Kiel, Kiel, Germany
| | - Christoph Höller
- Department of Dermatology, Medical University of Vienna, Austria
| | - Lidija Kandolf
- Department of Dermatology, Faculty of Medicine, Military Medical Academy, Belgrade, Serbia
| | - Nicole W J Kellerners-Smeets
- GROW-School for Oncology and Reproduction, Maastricht University, Maastricht, Netherlands; Department of Dermatology, Maastricht University Medical Centre, Maastricht, Netherlands
| | - Aimilios Lallas
- First Department of Dermatology, Aristotle University, Thessaloniki, Greece
| | - Ulrike Leiter
- Centre for Dermatooncology, Department of Dermatology, Eberhard-Karls University, Tuebingen, Germany
| | - Josep Malvehy
- Department of Dermatology, Hospital Clínic de Barcelona (Melanoma Unit), University of Barcelona, IDIBAPS, Barcelona & CIBERER, Barcelona, Spain
| | - Branka Marinović
- Department of Dermatology and Venereology, University Hospital Center Zagreb, Croatia
| | - Zeljko Mijuskovic
- Department of Dermatology, Faculty of Medicine, Military Medical Academy, Belgrade, Serbia
| | - David Moreno-Ramirez
- Dermatology. Medicine School, University of Seville, University Hospital Virgen Macarena, Seville-Spain
| | - Eduardo Nagore
- Department of Dermatology, Instituto Valenciano de Oncologia, Valencia, Spain
| | | | - Alexander J Stratigos
- First Department of Dermatology-Venereology, National and Kapodistrian University of Athens, School of Medicine, Andreas Sygros Hospital, Athens, Greece
| | - Eggert Stockfleth
- Department of Dermatology, Skin Cancer Center, Ruhr-University Bochum, 44791 Bochum, Germany
| | - Luca Tagliaferri
- Fondazione Policlinico Universitario A. Gemelli IRCCS, UOC di Radioterapia, Dipartimento di Scienze Radiologiche, Radioterapiche ed Ematologiche, Rome, Italy
| | - Myrto Trakatelli
- Second Department of Dermatology, Aristotle University Medical School, Papageorgiou General Hospital, Thessaloniki, Greece
| | - Ricardo Vieira
- Coimbra Hospital and Universitary Centre, Coimbra, Portugal
| | - Iris Zalaudek
- Dermatology Clinic, University of Trieste, Trieste, Italy
| | - Claus Garbe
- Centre for Dermatooncology, Department of Dermatology, Eberhard-Karls University, Tuebingen, Germany
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20
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Yang Y, Gomez N, Infarinato N, Adam RC, Sribour M, Baek I, Laurin M, Fuchs E. The pioneer factor SOX9 competes for epigenetic factors to switch stem cell fates. Nat Cell Biol 2023; 25:1185-1195. [PMID: 37488435 PMCID: PMC10415178 DOI: 10.1038/s41556-023-01184-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2023] [Accepted: 06/08/2023] [Indexed: 07/26/2023]
Abstract
During development, progenitors simultaneously activate one lineage while silencing another, a feature highly regulated in adult stem cells but derailed in cancers. Equipped to bind cognate motifs in closed chromatin, pioneer factors operate at these crossroads, but how they perform fate switching remains elusive. Here we tackle this question with SOX9, a master regulator that diverts embryonic epidermal stem cells (EpdSCs) into becoming hair follicle stem cells. By engineering mice to re-activate SOX9 in adult EpdSCs, we trigger fate switching. Combining epigenetic, proteomic and functional analyses, we interrogate the ensuing chromatin and transcriptional dynamics, slowed temporally by the mature EpdSC niche microenvironment. We show that as SOX9 binds and opens key hair follicle enhancers de novo in EpdSCs, it simultaneously recruits co-factors away from epidermal enhancers, which are silenced. Unhinged from its normal regulation, sustained SOX9 subsequently activates oncogenic transcriptional regulators that chart the path to cancers typified by constitutive SOX9 expression.
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Affiliation(s)
- Yihao Yang
- Howard Hughes Medical Institute, Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, NY, USA
| | - Nicholas Gomez
- Howard Hughes Medical Institute, Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, NY, USA
- Allen Institute for Cell Sciences, Seattle, WA, USA
| | - Nicole Infarinato
- Howard Hughes Medical Institute, Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, NY, USA
- PRECISIONscientia, Yardley, PA, USA
| | - Rene C Adam
- Howard Hughes Medical Institute, Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, NY, USA
- Regeneron Pharmaceuticals, Tarrytown, NY, USA
| | - Megan Sribour
- Howard Hughes Medical Institute, Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, NY, USA
| | - Inwha Baek
- Howard Hughes Medical Institute, Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, NY, USA
- Kyung Hee University, Seoul, South Korea
| | - Mélanie Laurin
- Howard Hughes Medical Institute, Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, NY, USA
- CHU de Québec-Université Laval Research Center, Quebec City, Quebec, Canada
| | - Elaine Fuchs
- Howard Hughes Medical Institute, Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, NY, USA.
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21
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Rybski KJ, Zengin HB, Smoller BR. TRPS1: A Marker of Follicular Differentiation. Dermatopathology (Basel) 2023; 10:173-183. [PMID: 37366800 DOI: 10.3390/dermatopathology10020025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Revised: 06/05/2023] [Accepted: 06/12/2023] [Indexed: 06/28/2023] Open
Abstract
The trichorhinophalangeal syndrome type 1 (TRPS1) immunohistochemical (IHC) stain has increased in use in recent years as a marker for breast carcinomas. The TRPS1 gene is involved in various tissues, including the growth and differentiation of hair follicles. This article seeks to evaluate the IHC expression of TRPS1 in cutaneous neoplasms with follicular differentiation, such as trichoblastoma (TB), trichoepithelioma (TE), and basal cell carcinoma (BCC). IHC studies were performed on 13 TBs, 15 TEs, and 15 BCCs with an antibody against TRPS1. The study found a variable staining expression of TRPS1 in the tumor nests of TB, TE, and BCC. BCCs were distinct in that none of the BCCs demonstrated intermediate or high positivity, while TBs and TEs showed intermediate-to-high positivity in 5/13 (38%) and 3/15 (20%) of cases, respectively. We observed a distinct staining pattern among the mesenchymal cells of TB and TE. We found that TRPS1 highlighted perifollicular mesenchymal cells adjacent to the nests of TB and TE tumor cells. This staining pattern was absent in BCCs, where only scattered stromal cells were positive for TRPS1. Papillary mesenchymal bodies were also highlighted by TRPS1 in TB and TE. TRPS1 stained various parts of the normal hair follicle, including the nuclei of cells in the germinal matrix, outer root sheaths, and hair papillae. TRPS1 may be a useful IHC marker for follicular differentiation.
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Affiliation(s)
- Kristin J Rybski
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Hatice B Zengin
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Bruce R Smoller
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA
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22
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Kurokami Y, Ishitsuka Y, Kiyohara E, Tanemura A, Fujimoto M. c-FOS Expression in Metastatic Basal Cell Carcinoma with Spontaneous Basosquamous Transition. Acta Derm Venereol 2023; 103:adv5347. [PMID: 36994778 PMCID: PMC10108615 DOI: 10.2340/actadv.v103.5347] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Accepted: 03/10/2023] [Indexed: 03/31/2023] Open
Abstract
Abstract is missing (Short communication)
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Affiliation(s)
- Yu Kurokami
- Department of Dermatology, Faculty of Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, Japan
| | - Yosuke Ishitsuka
- Department of Dermatology, Faculty of Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, Japan.
| | - Eiji Kiyohara
- Department of Dermatology, Faculty of Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, Japan
| | - Atsushi Tanemura
- Department of Dermatology, Faculty of Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, Japan
| | - Manabu Fujimoto
- Department of Dermatology, Faculty of Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, Japan
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23
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Yamazaki K, Maejima M, Saeki H, Osada SI. Recurrence or de novo? Intradermal Basal Cell Carcinoma of the Scrotum: A Report of Two Cases. Dermatopathology (Basel) 2023; 10:128-135. [PMID: 37092530 PMCID: PMC10123599 DOI: 10.3390/dermatopathology10020019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 03/23/2023] [Accepted: 03/24/2023] [Indexed: 03/30/2023] Open
Abstract
Basal cell carcinoma (BCC) is the most common cutaneous malignancy, usually occurring in sun-exposed areas. Although BCC in the scrotal region is uncommon, it carries a higher risk of metastasis than BCC at other sites. Here, we report two cases of BCC that developed in the scrotal region: Case 1 presented as a superficial nodule and Case 2 as a subcutaneous nodule. Histopathologically, both tumors lacked continuity with the surface epidermis and formed an intradermal nodule. In Case 1, BCC occurred for the first time and presumably developed de novo. Case 2 underwent excision of a scrotal BCC 5 years previously, and the histopathological diagnosis at that time was nodular BCC. However, when the original specimen was re-examined, it was determined that, although the tumor had been completely resected, part of the lesion had moved away from the nodular area to represent a micronodular phenotype, an aggressive BCC subtype. We hypothesized that partial evolution from a nodular to a micronodular phenotype may have contributed to the recurrence of BCC in Case 2.
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24
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Soutou B, Massih C, Sleilaty G, Trak-Smayra V, Nasr M, Helou J, Hokayem N, Ferran F, Sleilati FH, Stéphan F, Halabi-Tawil M, Tomb R. Clinical and pathological features associated with high-risk, multiple, and recurrent basal cell carcinomas: a retrospective cohort analysis from the Levantine coast of the Mediterranean Sea. Arch Dermatol Res 2023; 315:51-59. [PMID: 35059802 DOI: 10.1007/s00403-021-02316-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 11/17/2021] [Accepted: 12/07/2021] [Indexed: 01/07/2023]
Abstract
Basal cell carcinoma (BCC) data coming from the Levantine coast of the Mediterranean Sea are limited. The study aimed to primarily analyze the demographic, clinical, pathological, and prognostic characteristics of BCC in this region of the world and secondarily identify features associated with high-risk, recurrent, or multiple BCCs. Patients with at least one diagnosis of BCC registered in the pathology department between January 2015 and December 2019 were included in this analytical retrospective single-center cohort study. Patients with basal cell nevus syndrome were excluded. Patients' characteristics and pathological features were collected through file check for a first analysis. Risk factors and evolution were sought through a phone call interview for the second analysis. The first analysis included 506 BCCs corresponding to 365 patients with a mean age of 65 ± 15 years, twenty-two (6%) were less than 40 years old, 180 (49.3%) were women, and 85 (23.3%) had two or more BCCs. The second analysis included 279 BCCs corresponding to 205 patients. Periorificial and infiltrative BCCs were more frequent in men. Periorificial tumors were more frequently nodular or infiltrative and were associated with recurrence. Tumors with perineural involvement were histologically never nodular nor superficial. Recurrence was more frequent in BCCs having periorificial location, a size larger than 2 cm, or an infiltrative subtype. Multiple BCCs were more frequent in patients with light skin type or familial history of skin cancer. High-risk BCCs were more common in patients with low sun exposure.
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Affiliation(s)
- Boutros Soutou
- Dermatology department, School of Medicine, Université Saint-Joseph, and Hôtel-Dieu de France University Hospital, Hôtel-Dieu de France, Boulevard Alfred Naccache, Beirut, 16-6830, Lebanon.
| | - Carine Massih
- Dermatology department, School of Medicine, Université Saint-Joseph, and Hôtel-Dieu de France University Hospital, Hôtel-Dieu de France, Boulevard Alfred Naccache, Beirut, 16-6830, Lebanon.
| | - Ghassan Sleilaty
- Statistics department, School of Medicine, Université Saint-Joseph, and Hôtel-Dieu de France University Hospital, Beirut, Lebanon
| | - Viviane Trak-Smayra
- Pathology department, School of Medicine, Université Saint-Joseph, and Hôtel-Dieu de France University Hospital, Beirut, Lebanon
| | - Marwan Nasr
- Plastic and Reconstructive Surgery Department, School of Medicine, Université Saint-Joseph, and Hôtel-Dieu de France University Hospital, Beirut, Lebanon
| | - Josiane Helou
- Dermatology department, School of Medicine, Université Saint-Joseph, and Hôtel-Dieu de France University Hospital, Hôtel-Dieu de France, Boulevard Alfred Naccache, Beirut, 16-6830, Lebanon
| | - Nabil Hokayem
- Plastic and Reconstructive Surgery Department, School of Medicine, Université Saint-Joseph, and Hôtel-Dieu de France University Hospital, Beirut, Lebanon
| | - Fady Ferran
- Plastic and Reconstructive Surgery Department, School of Medicine, Université Saint-Joseph, and Hôtel-Dieu de France University Hospital, Beirut, Lebanon
| | - Fadi H Sleilati
- Plastic and Reconstructive Surgery Department, School of Medicine, Université Saint-Joseph, and Hôtel-Dieu de France University Hospital, Beirut, Lebanon
| | - Farid Stéphan
- Dermatology department, School of Medicine, Université Saint-Joseph, and Hôtel-Dieu de France University Hospital, Hôtel-Dieu de France, Boulevard Alfred Naccache, Beirut, 16-6830, Lebanon
| | - Maya Halabi-Tawil
- Dermatology department, School of Medicine, Université Saint-Joseph, and Hôtel-Dieu de France University Hospital, Hôtel-Dieu de France, Boulevard Alfred Naccache, Beirut, 16-6830, Lebanon
| | - Roland Tomb
- Dermatology department, School of Medicine, Université Saint-Joseph, and Hôtel-Dieu de France University Hospital, Hôtel-Dieu de France, Boulevard Alfred Naccache, Beirut, 16-6830, Lebanon
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25
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Saha B, Vannucci L, Saha B, Tenti P, Baral R. Evolvability and emergence of tumor heterogeneity as a space-time function. Cytokine 2023; 161:156061. [PMID: 36252436 DOI: 10.1016/j.cyto.2022.156061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 09/20/2022] [Accepted: 09/30/2022] [Indexed: 11/22/2022]
Abstract
The loss of control of cell proliferation, apoptosis regulation and contact inhibition leads to tumor development. While benign tumors are restricted to their primary space, i.e. where these tumors first originate, the metastatic tumors not only disseminate- facilitated by hypoxia-driven neovascularization- to distant secondary sites but also show substantial changes in metabolism, tissue architectures, gene expression profiles and immune phenotypes. All these alterations result in radio-, chemo- and immune-resistance rendering these metastatic tumor cells refractory to therapy. Since the beginning of the transformation, these factors- which influence each other- are incorporated to the developing and metastasizing tumor. As a result, the complexities in the heterogeneity of tumor progressively increase. This space-time function in the heterogeneity of tumors is generated by various conditions and factors at the genetic as well as microenvironmental levels, for example, endogenous retroviruses, methylation and epigenetic dysregulation that may be etiology-specific, cancer associated inflammation, remodeling of the extracellular matrix and mesenchymal cell shifted functions. On the one hand, these factors may cause de-differentiation of the tumor cells leading to cancer stem cells that contribute to radio-, chemo- and immune-resistance and recurrence of tumors. On the other hand, they may also enhance the heterogeneity under specific microenvironment-driven proliferation. In this editorial, we intend to underline the importance of heterogeneity in cancer progress, its evaluation and its use in correlation with the tumor evolution in a specific patient as a field of research for achieving precise patient-tailored treatments and amelioration of diagnostic (monitoring) tools and prognostic capacity.
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Affiliation(s)
- Bhaskar Saha
- National Centre for Cell Science, Ganeshkhind, Pune 411007, India.
| | - Luca Vannucci
- Institute of Microbiology, Czech Academy of Sciences, Videnska 1083, Praha, Czech Republic.
| | - Baibaswata Saha
- Institute of Microbiology, Czech Academy of Sciences, Videnska 1083, Praha, Czech Republic
| | - Paolo Tenti
- Institute of Microbiology, Czech Academy of Sciences, Videnska 1083, Praha, Czech Republic
| | - Rathindranath Baral
- Chittaranjan National Cancer Institute, Shyamaprasad Mukherjee Road, Calcutta 700026, India.
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26
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Krieter M, Schultz E. [Current Management of Basal Cell Carcinoma]. Laryngorhinootologie 2022; 101:969-978. [PMID: 36513089 DOI: 10.1055/a-1861-7077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
AIM OF STUDY We present the current standard in diagnosis and treatment of basal cell carcinoma. Useful procedures for clinical management should be derived from this. METHODS A systematic literature search was carried out in the PubMed online database. The collected information was analyzed and evaluated. An overall concept was created from the gained knowledge. RESULTS Basal cell carcinoma is the most common tumor in humans and its incidence is expected to increase in the future. When managing the disease, a one-dimensional orientation towards the clinical or histological subtype is not sufficient because of the heterogeneity of the tumor. The primary implementation of risk stratification, which is decisive for the further diagnostic and therapeutic steps, is becoming increasingly important. The gold standard in treatment continues to be the surgical procedure, which should be carried out using micrographically controlled surgery if possible. In addition, there are other therapeutic methods such as radiotherapy or a number of topical therapy options (photodynamic therapy, cryotherapy, application of 5-fluorouracil or imiquimod), which can be used in certain cases. Hedgehog inhibitors are also effective drugs for advanced or metastatic basal cell carcinoma. Practitioners have gained several years of experience with regard to effectiveness and handling of adverse events. With the PD-1 inhibitor cemiplimab, another therapeutic option for inoperable or metastatic tumors has been available since June 2021. CONCLUSION Basal cell carcinoma will continue to gain in relevance in daily dermatological practice in the coming years. A structured approach to the assessment of the existing risk category of the tumor and the subsequent determination of the optimal therapy regimen are of central importance. Advanced or metastatic tumors no longer represent a hopeless situation for the patient. With long-termhedgehog therapy, an adapted dosage scheme can avoid discontinuation of therapy due to side effects. The therapeutic potential of the PD-1 inhibitor cemiplimab can also be used with the side effect profile known from other types of skin cancer.
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Affiliation(s)
- Manuel Krieter
- Universitätsklinik für Dermatologie, Paracelsus Medizinische Privatuniversität Nürnberg, Nürnberg, Deutschland
| | - Erwin Schultz
- Universitätsklinik für Dermatologie, Paracelsus Medizinische Privatuniversität Nürnberg, Nürnberg, Deutschland
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27
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Morgan HJ, Rees E, Lanfredini S, Powell KA, Gore J, Gibbs A, Lovatt C, Davies GE, Olivero C, Shorning BY, Tornillo G, Tonks A, Darley R, Wang EC, Patel GK. CD200 ectodomain shedding into the tumor microenvironment leads to NK cell dysfunction and apoptosis. J Clin Invest 2022; 132:150750. [PMID: 36074574 PMCID: PMC9621138 DOI: 10.1172/jci150750] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Accepted: 09/01/2022] [Indexed: 11/24/2022] Open
Abstract
The basis of immune evasion, a hallmark of cancer, can differ even when cancers arise from one cell type such as in the human skin keratinocyte carcinomas: basal and squamous cell carcinoma. Here we showed that the basal cell carcinoma tumor-initiating cell surface protein CD200, through ectodomain shedding, was responsible for the near absence of NK cells within the basal cell carcinoma tumor microenvironment. In situ, CD200 underwent ectodomain shedding by metalloproteinases MMP3 and MMP11, which released biologically active soluble CD200 into the basal cell carcinoma microenvironment. CD200 bound its cognate receptor on NK cells to suppress MAPK pathway signaling that in turn blocked indirect (IFN-γ release) and direct cell killing. In addition, reduced ERK phosphorylation relinquished negative regulation of PPARγ-regulated gene transcription and led to membrane accumulation of the Fas/FADD death receptor and its ligand, FasL, which resulted in activation-induced apoptosis. Blocking CD200 inhibition of MAPK or PPARγ signaling restored NK cell survival and tumor cell killing, with relevance to many cancer types. Our results thus uncover a paradigm for CD200 as a potentially novel and targetable NK cell-specific immune checkpoint, which is responsible for NK cell-associated poor outcomes in many cancers.
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Affiliation(s)
- Huw J Morgan
- European Cancer Stem Cell Research Institute, School of Biosciences
| | - Elise Rees
- European Cancer Stem Cell Research Institute, School of Biosciences
| | | | - Kate A Powell
- European Cancer Stem Cell Research Institute, School of Biosciences
| | - Jasmine Gore
- European Cancer Stem Cell Research Institute, School of Biosciences
| | - Alex Gibbs
- European Cancer Stem Cell Research Institute, School of Biosciences
| | - Charlotte Lovatt
- European Cancer Stem Cell Research Institute, School of Biosciences
| | - Gemma E Davies
- European Cancer Stem Cell Research Institute, School of Biosciences
| | - Carlotta Olivero
- European Cancer Stem Cell Research Institute, School of Biosciences
| | - Boris Y Shorning
- European Cancer Stem Cell Research Institute, School of Biosciences
| | - Giusy Tornillo
- European Cancer Stem Cell Research Institute, School of Biosciences
| | - Alex Tonks
- Department of Haematology, Division of Cancer & Genetics, School of Medicine, and
| | - Richard Darley
- Department of Haematology, Division of Cancer & Genetics, School of Medicine, and
| | - Eddie Cy Wang
- Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom
| | - Girish K Patel
- European Cancer Stem Cell Research Institute, School of Biosciences
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28
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Ramchatesingh B, Martínez Villarreal A, Arcuri D, Lagacé F, Setah SA, Touma F, Al-Badarin F, Litvinov IV. The Use of Retinoids for the Prevention and Treatment of Skin Cancers: An Updated Review. Int J Mol Sci 2022; 23:ijms232012622. [PMID: 36293471 PMCID: PMC9603842 DOI: 10.3390/ijms232012622] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 10/12/2022] [Accepted: 10/13/2022] [Indexed: 11/21/2022] Open
Abstract
Retinoids are natural and synthetic vitamin A derivatives that are effective for the prevention and the treatment of non-melanoma skin cancers (NMSC). NMSCs constitute a heterogenous group of non-melanocyte-derived skin cancers that impose substantial burdens on patients and healthcare systems. They include entities such as basal cell carcinoma and cutaneous squamous cell carcinoma (collectively called keratinocyte carcinomas), cutaneous lymphomas and Kaposi’s sarcoma among others. The retinoid signaling pathway plays influential roles in skin physiology and pathology. These compounds regulate diverse biological processes within the skin, including proliferation, differentiation, angiogenesis and immune regulation. Collectively, retinoids can suppress skin carcinogenesis. Both topical and systemic retinoids have been investigated in clinical trials as NMSC prophylactics and treatments. Desirable efficacy and tolerability in clinical trials have prompted health regulatory bodies to approve the use of retinoids for NMSC management. Acceptable off-label uses of these compounds as drugs for skin cancers are also described. This review is a comprehensive outline on the biochemistry of retinoids, their activities in the skin, their effects on cancer cells and their adoption in clinical practice.
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Affiliation(s)
| | | | - Domenico Arcuri
- Faculty of Medicine and Health Sciences, McGill University, Montreal, QC H4A 3J1, Canada
| | - François Lagacé
- Faculty of Medicine and Health Sciences, McGill University, Montreal, QC H4A 3J1, Canada
- Division of Dermatology, McGill University Health Center, Montreal, QC H4A 3J1, Canada
| | - Samy Abu Setah
- Faculty of Medicine and Health Sciences, McGill University, Montreal, QC H4A 3J1, Canada
| | - Fadi Touma
- Faculty of Medicine and Health Sciences, McGill University, Montreal, QC H4A 3J1, Canada
| | - Faris Al-Badarin
- Faculté de Médicine, Université Laval, Québec, QC G1V 0V6, Canada
| | - Ivan V. Litvinov
- Division of Experimental Medicine, McGill University, Montreal, QC H4A 3J1, Canada
- Faculty of Medicine and Health Sciences, McGill University, Montreal, QC H4A 3J1, Canada
- Division of Dermatology, McGill University Health Center, Montreal, QC H4A 3J1, Canada
- Correspondence:
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29
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Molecular Mechanisms and Targeted Therapies of Advanced Basal Cell Carcinoma. Int J Mol Sci 2022; 23:ijms231911968. [PMID: 36233269 PMCID: PMC9570397 DOI: 10.3390/ijms231911968] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Revised: 09/18/2022] [Accepted: 09/19/2022] [Indexed: 11/23/2022] Open
Abstract
Among human cutaneous malignancies, basal cell carcinoma is the most common. Solid advances in unveiling the molecular mechanisms of basal cell carcinoma have emerged in recent years. In Gorlin syndrome, which shows basal cell carcinoma predisposition, identification of the patched 1 gene (PTCH1) mutation was a dramatic breakthrough in understanding the carcinogenesis of basal cell carcinoma. PTCH1 plays a role in the hedgehog pathway, and dysregulations of this pathway are known to be crucial for the carcinogenesis of many types of cancers including sporadic as well as hereditary basal cell carcinoma. In this review, we summarize the clinical features, pathological features and hedgehog pathway as applied in basal cell carcinoma. Other crucial molecules, such as p53 and melanocortin-1 receptor are also discussed. Due to recent advances, therapeutic strategies based on the precise molecular mechanisms of basal cell carcinoma are emerging. Target therapies and biomarkers are also discussed.
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Jiang J. Hedgehog signaling mechanism and role in cancer. Semin Cancer Biol 2022; 85:107-122. [PMID: 33836254 PMCID: PMC8492792 DOI: 10.1016/j.semcancer.2021.04.003] [Citation(s) in RCA: 91] [Impact Index Per Article: 30.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 03/25/2021] [Accepted: 04/02/2021] [Indexed: 12/12/2022]
Abstract
Cell-cell communication through evolutionarily conserved signaling pathways governs embryonic development and adult tissue homeostasis. Deregulation of these signaling pathways has been implicated in a wide range of human diseases including cancer. One such pathway is the Hedgehog (Hh) pathway, which was originally discovered in Drosophila and later found to play a fundamental role in human development and diseases. Abnormal Hh pathway activation is a major driver of basal cell carcinomas (BCC) and medulloblastoma. Hh exerts it biological influence through a largely conserved signal transduction pathway from the activation of the GPCR family transmembrane protein Smoothened (Smo) to the conversion of latent Zn-finger transcription factors Gli/Ci proteins from their repressor (GliR/CiR) to activator (GliA/CiA) forms. Studies from model organisms and human patients have provided deep insight into the Hh signal transduction mechanisms, revealed roles of Hh signaling in a wide range of human cancers, and suggested multiple strategies for targeting this pathway in cancer treatment.
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Affiliation(s)
- Jin Jiang
- Department of Molecular Biology and Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, 75390, USA.
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Maguire G. Chronic inflammation induced by microneedling and the use of bone marrow stem cell cytokines. J Tissue Viability 2022; 31:687-692. [DOI: 10.1016/j.jtv.2022.08.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 08/07/2022] [Accepted: 08/16/2022] [Indexed: 10/14/2022]
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Melica ME, Antonelli G, Semeraro R, Angelotti ML, Lugli G, Landini S, Ravaglia F, La Regina G, Conte C, De Chiara L, Peired AJ, Mazzinghi B, Donati M, Molli A, Steiger S, Magi A, Bartalucci N, Raglianti V, Guzzi F, Maggi L, Annunziato F, Burger A, Lazzeri E, Anders HJ, Lasagni L, Romagnani P. Differentiation of crescent-forming kidney progenitor cells into podocytes attenuates severe glomerulonephritis in mice. Sci Transl Med 2022; 14:eabg3277. [PMID: 35947676 PMCID: PMC7614034 DOI: 10.1126/scitranslmed.abg3277] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Crescentic glomerulonephritis is characterized by vascular necrosis and parietal epithelial cell hyperplasia in the space surrounding the glomerulus, resulting in the formation of crescents. Little is known about the molecular mechanisms driving this process. Inducing crescentic glomerulonephritis in two Pax2Cre reporter mouse models revealed that crescents derive from clonal expansion of single immature parietal epithelial cells. Preemptive and delayed histone deacetylase inhibition with panobinostat, a drug used to treat hematopoietic stem cell disorders, attenuated crescentic glomerulonephritis with recovery of kidney function in the two mouse models. Three-dimensional confocal microscopy and stimulated emission depletion superresolution imaging of mouse glomeruli showed that, in addition to exerting an anti-inflammatory and immunosuppressive effect, panobinostat induced differentiation of an immature hyperplastic parietal epithelial cell subset into podocytes, thereby restoring the glomerular filtration barrier. Single-cell RNA sequencing of human renal progenitor cells in vitro identified an immature stratifin-positive cell subset and revealed that expansion of this stratifin-expressing progenitor cell subset was associated with a poor outcome in human crescentic glomerulonephritis. Treatment of human parietal epithelial cells in vitro with panobinostat attenuated stratifin expression in renal progenitor cells, reduced their proliferation, and promoted their differentiation into podocytes. These results offer mechanistic insights into the formation of glomerular crescents and demonstrate that selective targeting of renal progenitor cells can attenuate crescent formation and the deterioration of kidney function in crescentic glomerulonephritis in mice.
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Affiliation(s)
- Maria Elena Melica
- Excellence Centre for Research, Transfer and High Education for the development of DE NOVO Therapies (DENOTHE), University of Florence, Florence 50139, Italy,Department of Experimental and Clinical Biomedical Sciences “Mario Serio,” University of Florence, Florence 50139, Italy
| | - Giulia Antonelli
- Excellence Centre for Research, Transfer and High Education for the development of DE NOVO Therapies (DENOTHE), University of Florence, Florence 50139, Italy,Department of Experimental and Clinical Biomedical Sciences “Mario Serio,” University of Florence, Florence 50139, Italy
| | - Roberto Semeraro
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Maria Lucia Angelotti
- Excellence Centre for Research, Transfer and High Education for the development of DE NOVO Therapies (DENOTHE), University of Florence, Florence 50139, Italy,Department of Experimental and Clinical Biomedical Sciences “Mario Serio,” University of Florence, Florence 50139, Italy
| | - Gianmarco Lugli
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio,” University of Florence, Florence 50139, Italy,Nephrology and Dialysis Unit, Meyer Children’s Hospital, Florence 50139, Italy
| | - Samuela Landini
- Nephrology and Dialysis Unit, Meyer Children’s Hospital, Florence 50139, Italy
| | - Fiammetta Ravaglia
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio,” University of Florence, Florence 50139, Italy
| | - Gilda La Regina
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio,” University of Florence, Florence 50139, Italy
| | - Carolina Conte
- Excellence Centre for Research, Transfer and High Education for the development of DE NOVO Therapies (DENOTHE), University of Florence, Florence 50139, Italy,Department of Experimental and Clinical Biomedical Sciences “Mario Serio,” University of Florence, Florence 50139, Italy
| | - Letizia De Chiara
- Excellence Centre for Research, Transfer and High Education for the development of DE NOVO Therapies (DENOTHE), University of Florence, Florence 50139, Italy,Department of Experimental and Clinical Biomedical Sciences “Mario Serio,” University of Florence, Florence 50139, Italy
| | - Anna Julie Peired
- Excellence Centre for Research, Transfer and High Education for the development of DE NOVO Therapies (DENOTHE), University of Florence, Florence 50139, Italy,Department of Experimental and Clinical Biomedical Sciences “Mario Serio,” University of Florence, Florence 50139, Italy
| | - Benedetta Mazzinghi
- Nephrology and Dialysis Unit, Meyer Children’s Hospital, Florence 50139, Italy
| | - Marta Donati
- Nephrology and Dialysis Unit, Meyer Children’s Hospital, Florence 50139, Italy
| | - Alice Molli
- Nephrology and Dialysis Unit, Meyer Children’s Hospital, Florence 50139, Italy
| | - Stefanie Steiger
- Division of Nephrology, Medizinische Klinik and Poliklinik IV, Klinikum der LMU München, Munich 80336, Germany
| | - Alberto Magi
- Department of Information Engineering, University of Florence, Florence, Italy
| | - Niccolò Bartalucci
- Department of Experimental and Clinical Medicine, CRIMM, Center Research and Innovation of Myeloproliferative Neoplasms, AOUC, University of Florence, Florence 50139, Italy
| | - Valentina Raglianti
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio,” University of Florence, Florence 50139, Italy,Nephrology and Dialysis Unit, Meyer Children’s Hospital, Florence 50139, Italy
| | - Francesco Guzzi
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio,” University of Florence, Florence 50139, Italy,Nephrology and Dialysis Unit, Meyer Children’s Hospital, Florence 50139, Italy
| | - Laura Maggi
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Francesco Annunziato
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Alexa Burger
- Section of Developmental Biology, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Elena Lazzeri
- Excellence Centre for Research, Transfer and High Education for the development of DE NOVO Therapies (DENOTHE), University of Florence, Florence 50139, Italy,Department of Experimental and Clinical Biomedical Sciences “Mario Serio,” University of Florence, Florence 50139, Italy
| | - Hans-Joachim Anders
- Division of Nephrology, Medizinische Klinik and Poliklinik IV, Klinikum der LMU München, Munich 80336, Germany
| | - Laura Lasagni
- Excellence Centre for Research, Transfer and High Education for the development of DE NOVO Therapies (DENOTHE), University of Florence, Florence 50139, Italy,Department of Experimental and Clinical Biomedical Sciences “Mario Serio,” University of Florence, Florence 50139, Italy,Corresponding authors. and
| | - Paola Romagnani
- Excellence Centre for Research, Transfer and High Education for the development of DE NOVO Therapies (DENOTHE), University of Florence, Florence 50139, Italy,Department of Experimental and Clinical Biomedical Sciences “Mario Serio,” University of Florence, Florence 50139, Italy,Nephrology and Dialysis Unit, Meyer Children’s Hospital, Florence 50139, Italy,Corresponding authors. and
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The Contributions of Cancer-Testis and Developmental Genes to the Pathogenesis of Keratinocyte Carcinomas. Cancers (Basel) 2022; 14:cancers14153630. [PMID: 35892887 PMCID: PMC9367444 DOI: 10.3390/cancers14153630] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 07/21/2022] [Accepted: 07/22/2022] [Indexed: 11/17/2022] Open
Abstract
Simple Summary In addition to mutations, ectopically-expressed genes are emerging as important contributors to cancer development. Efforts to characterize the expression patterns in cancers of gamete-restricted cancer-testis antigens and developmentally-restricted genes are underway, revealing these genes to be putative biomarkers and therapeutic targets for various malignancies. Basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC) are two highly-prevalent non-melanoma skin cancers that result in considerable burden on patients and our health system. To optimize disease prognostication and treatment, it is necessary to further classify the molecular complexity of these malignancies. This review describes the expression patterns and functions of cancer-testis antigens and developmentally-restricted genes in BCC and cSCC tumors. A large number of cancer-testis antigens and developmental genes exhibit substantial expression levels in BCC and cSCC. These genes have been shown to contribute to several aspects of cancer biology, including tumorigenesis, differentiation, invasion and responses to anti-cancer therapy. Abstract Keratinocyte carcinomas are among the most prevalent malignancies worldwide. Basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC) are the two cancers recognized as keratinocyte carcinomas. The standard of care for treating these cancers includes surgery and ablative therapies. However, in recent years, targeted therapies (e.g., cetuximab for cSCC and vismodegib/sonidegib for BCC) have been used to treat advanced disease as well as immunotherapy (e.g., cemiplimab). These treatments are expensive and have significant toxicities with objective response rates approaching ~50–65%. Hence, there is a need to dissect the molecular pathogenesis of these cancers to identify novel biomarkers and therapeutic targets to improve disease management. Several cancer-testis antigens (CTA) and developmental genes (including embryonic stem cell factors and fetal genes) are ectopically expressed in BCC and cSCC. When ectopically expressed in malignant tissues, functions of these genes may be recaptured to promote tumorigenesis. CTAs and developmental genes are emerging as important players in the pathogenesis of BCC and cSCC, positioning themselves as attractive candidate biomarkers and therapeutic targets requiring rigorous testing. Herein, we review the current research and offer perspectives on the contributions of CTAs and developmental genes to the pathogenesis of keratinocyte carcinomas.
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Recurrent cutaneous basal cell carcinoma after surgical excision: A retrospective clinicopathological study. Ann Med Surg (Lond) 2022; 78:103877. [PMID: 35734696 PMCID: PMC9207056 DOI: 10.1016/j.amsu.2022.103877] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 05/18/2022] [Accepted: 05/22/2022] [Indexed: 11/21/2022] Open
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Eight Years of Real-Life Experience with Smoothened Inhibitors in a Swiss Tertiary Skin Referral Center. Cancers (Basel) 2022; 14:cancers14102496. [PMID: 35626100 PMCID: PMC9139771 DOI: 10.3390/cancers14102496] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 05/12/2022] [Accepted: 05/13/2022] [Indexed: 12/04/2022] Open
Abstract
Simple Summary Vismodegib and sonidegib are targeted therapies inhibiting the hedgehog pathway, a key driver in the pathogenesis of basal cell carcinoma (BCC). Hedgehog inhibitors (HhIs) are first-line therapy for locally advanced basal cell carcinoma (laBCC), metastatic basal cell carcinoma (mBCC) and multiple BCCs, when surgery and radiotherapy are no longer feasible. Safety and efficacy of the HhIs vismodegib and sonidegib have been shown in large prospective clinical trials. However, treatment of advanced basal cell carcinoma (aBCC) in daily practice includes patients who do not meet strict inclusion criteria and poses an additional challenge for treating physicians. This study aims to give an insight into a real-world experience in our tertiary skin referral center. Abstract Background: The hedgehog inhibitors vismodegib and sonidegib are approved for the treatment of advanced basal cell carcinoma. This study reports the experiences with these therapies in a tertiary skin referral center in daily practice. Methods: A retrospective, observational, single-center study analyzing medical records of patients with aBCC treated with a smoothened (SMO) inhibitor outside a clinical trial for at least one month between 2013 and 2021. Results: In total, 33 patients were included: 21 (64%) patients were treated with vismodegib, 3 (9%) patients with sonidegib and 9 (27%) patients with both treatments subsequently. With vismodegib, the best overall response was complete response (CR) in 33% cases, and partial response (PR) in 33% cases. Under sonidegib, 42% patients achieved CR and 17% PR. Mean duration to next treatment was 33 and 14 months for vismodegib and sonidegib, respectively. Adverse events varied in frequency between continuous and intermittent dosing and they were the most common reason for therapy discontinuation. Conclusions: Our real-world data illustrate the pitfalls and benefits of HhIs as well as the impact of different dosing regimens on adverse events, patient adherence and response. Treatment duration remains limited by adverse events and resistance. Additional treatment options, including immunotherapy and drug combinations, are needed.
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Trieu KG, Tsai SY, Eberl M, Ju V, Ford NC, Doane OJ, Peterson JK, Veniaminova NA, Grachtchouk M, Harms PW, Swartling FJ, Dlugosz AA, Wong SY. Basal cell carcinomas acquire secondary mutations to overcome dormancy and progress from microscopic to macroscopic disease. Cell Rep 2022; 39:110779. [PMID: 35508126 PMCID: PMC9127636 DOI: 10.1016/j.celrep.2022.110779] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 03/14/2022] [Accepted: 04/12/2022] [Indexed: 12/11/2022] Open
Abstract
Basal cell carcinomas (BCCs) frequently possess immense mutational burdens; however, the functional significance of most of these mutations remains unclear. Here, we report that loss of Ptch1, the most common mutation that activates upstream Hedgehog (Hh) signaling, initiates the formation of nascent BCC-like tumors that eventually enter into a dormant state. However, rare tumors that overcome dormancy acquire the ability to hyperactivate downstream Hh signaling through a variety of mechanisms, including amplification of Gli1/2 and upregulation of Mycn. Furthermore, we demonstrate that MYCN overexpression promotes the progression of tumors induced by loss of Ptch1. These findings suggest that canonical mutations that activate upstream Hh signaling are necessary, but not sufficient, for BCC to fully progress. Rather, tumors likely acquire secondary mutations that further hyperactivate downstream Hh signaling in order to escape dormancy and enter a trajectory of uncontrolled expansion. Trieu et al. generate BCC mouse models in which rare macroscopic tumors form alongside numerous failed microscopic lesions. Successful macroscopic tumors acquire secondary changes that elevate Gli1, Gli2, and/or Mycn levels, causing hyperactivation of downstream Hedgehog (Hh) signaling. Loss of p53 and Notch1 also contributes to tumor progression.
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Affiliation(s)
- Kenneth G Trieu
- Department of Dermatology, Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Shih-Ying Tsai
- Department of Dermatology, Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Markus Eberl
- Department of Dermatology, Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Virginia Ju
- Department of Dermatology, Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Noah C Ford
- Department of Dermatology, Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Owen J Doane
- Department of Dermatology, Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Jamie K Peterson
- Department of Dermatology, Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Natalia A Veniaminova
- Department of Dermatology, Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Marina Grachtchouk
- Department of Dermatology, Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Paul W Harms
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Dermatology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Fredrik J Swartling
- Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, 751 05 Uppsala, Sweden
| | - Andrzej A Dlugosz
- Department of Dermatology, Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Sunny Y Wong
- Department of Dermatology, Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA.
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Peng J, Chen H, Zhang B. Nerve–stem cell crosstalk in skin regeneration and diseases. Trends Mol Med 2022; 28:583-595. [DOI: 10.1016/j.molmed.2022.04.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 04/11/2022] [Accepted: 04/12/2022] [Indexed: 11/30/2022]
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Wang J, He J, Zhu M, Han Y, Yang R, Liu H, Xu X, Chen X. Cellular Heterogeneity and Plasticity of Skin Epithelial Cells in Wound Healing and Tumorigenesis. Stem Cell Rev Rep 2022; 18:1912-1925. [PMID: 35143021 PMCID: PMC9391238 DOI: 10.1007/s12015-021-10295-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/27/2021] [Indexed: 12/20/2022]
Abstract
Cellular differentiation, the fundamental hallmark of cells, plays a critical role in homeostasis. And stem cells not only regulate the process where embryonic stem cells develop into a complete organism, but also replace ageing or damaged cells by proliferation, differentiation and migration. In characterizing distinct subpopulations of skin epithelial cells, stem cells show large heterogeneity and plasticity for homeostasis, wound healing and tumorigenesis. Epithelial stem cells and committed progenitors replenish each other or by themselves owing to the remarkable plasticity and heterogeneity of epidermal cells under certain circumstance. The development of new assay methods, including single-cell RNA sequence, lineage tracing assay, intravital microscopy systems and photon-ablation assay, highlight the plasticity of epidermal stem cells in response to injure and tumorigenesis. However, the critical mechanisms and key factors that regulate cellular plasticity still need for further exploration. In this review, we discuss the recent insights about the heterogeneity and plasticity of epithelial stem cells in homeostasis, wound healing and skin tumorigenesis. Understanding how stem cells collaborate together to repair injury and initiate tumor will offer new solutions for relevant diseases. Schematic abstract of cellular heterogeneity and plasticity of skin epithelial cells in wound healing and tumorigenesis.
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Affiliation(s)
- Jingru Wang
- Department of Plastic Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China.,Department of Burn Surgery, First People's Hospital of Foshan, Foshan, China
| | - Jia He
- Department of Burn Surgery, First People's Hospital of Foshan, Foshan, China.,School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Guangzhou, China
| | - Meishu Zhu
- Department of Burn and Plastic Surgery, Second People's Hospital of Shenzhen, First Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen, China
| | - Yan Han
- The Yonghe Medical Group Limited Company, George Town, Cayman Islands
| | - Ronghua Yang
- Department of Burn Surgery, First People's Hospital of Foshan, Foshan, China
| | - Hongwei Liu
- Department of Plastic Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China.
| | - Xuejuan Xu
- Endocrinology Department, First People's Hospital of Foshan, Foshan, China.
| | - Xiaodong Chen
- Department of Burn Surgery, First People's Hospital of Foshan, Foshan, China.
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Singh K, Bailey-Lundberg JM. Murine Models for Lineage Tracing Cancer Initiating Cells. Methods Mol Biol 2022; 2435:181-193. [PMID: 34993947 DOI: 10.1007/978-1-0716-2014-4_13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
The process of cellular transformation involves acquisition of genetic mutations that disrupt parenchymal organization and promote unrestrained epithelial cell proliferation. In the context of transformation, recent advances using genetic lineage tracing have enabled scientists to study the behavior of neoplastic cells in their native habitat. Employing lineage tracing to understand mechanisms of transformation, including cell type-specific responses to inflammation, is an empirical method to use in the field of cancer prevention. Identifying new approaches to prevent cancer formation can be directly studied by indelibly labeling cells to trace their fate and understand at a molecular level how they respond to novel methods for testing cancer preventing agents.
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Affiliation(s)
- Kanchan Singh
- Department of Anesthesiology, McGovern Medical School, The University of Texas Health Science Center, Houston, TX, USA
| | - Jennifer M Bailey-Lundberg
- Department of Anesthesiology, McGovern Medical School, The University of Texas Health Science Center, Houston, TX, USA.
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Krieter M, Schultz E. Aktuelles Management des Basalzellkarzinoms. AKTUELLE DERMATOLOGIE 2021. [DOI: 10.1055/a-1487-3853] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Zusammenfassung
Ziel der Studie Der aktuelle Standard von Diagnostik und Therapie des Basalzellkarzinoms soll dargestellt werden. Hieraus sollen sinnvolle Vorgehensweisen für das klinische Management abgeleitet werden.
Methodik Es erfolgte eine systematische Literaturrecherche in der Online-Datenbank PubMed. Die gesammelten Informationen wurden analysiert und bewertet. Aus den gewonnenen Erkenntnissen wurde ein Gesamtkonzept erstellt.
Ergebnisse Das Basalzellkarzinom ist der häufigste Tumor des Menschen und die Inzidenz wird voraussichtlich künftig weiter zunehmen. Beim Management der Erkrankung wird eine eindimensionale Orientierung am klinischen bzw. histologischen Basalzellkarzinom-Subtyp der Heterogenität des Tumors nicht gerecht. Zunehmende Bedeutung gewinnt die primäre Durchführung einer Risikostratifizierung, die für die weiteren diagnostischen und therapeutischen Schritte maßgeblich ist. Goldstandard in der Behandlung bleibt weiterhin das operative Vorgehen, welches möglichst mittels mikrografisch kontrollierter Chirurgie erfolgen sollte. Daneben existieren weitere Therapieverfahren wie die Radiotherapie oder eine Reihe an topischen Therapieoptionen (photodynamische Therapie, Kryotherapie oder Applikation von 5-Fluoruracil bzw. Imiquimod), die in bestimmten Fällen zur Anwendung kommen können. Auch für fortgeschrittene oder metastasierte Basalzellkarzinome stehen mit den Hedgehog-Inhibitoren wirksame Medikamente zur Verfügung, für die inzwischen eine mehrjährige Anwendungserfahrung hinsichtlich Wirksamkeit und Umgang mit unerwünschten Ereignissen vorliegt. Mit den PD-1-Inhibitoren steht eine weitere systemische Therapieoption in Aussicht, deren Nutzen aktuell noch in klinischen Studien überprüft wird.
Schlussfolgerung Das Basalzellkarzinom wird in den kommenden Jahren weiter an Relevanz in der täglichen dermatologischen Praxis gewinnen. Eine strukturierte Herangehensweise zur Einschätzung der vorliegenden Risikokategorie des Tumors und die anschließende Festlegung des optimalen Therapieregimes sind von zentraler Bedeutung. Fortgeschrittene oder metastasierte Tumoren stellen keine aussichtslose Situation für den Patienten mehr dar. Durch adaptierte Dosierschemata kann ein nebenwirkungsbedingter Therapieabbruch unter langfristiger Hedgehog-Therapie vermieden werden. Das therapeutische Potenzial von PD-1-Inhibitoren könnte bald auch beim Basalzellkarzinom genutzt werden.
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Affiliation(s)
- Manuel Krieter
- Universitätsklinik für Dermatologie, Paracelsus Medizinische Privatuniversität Nürnberg, Deutschland
| | - Erwin Schultz
- Universitätsklinik für Dermatologie, Paracelsus Medizinische Privatuniversität Nürnberg, Deutschland
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Dasgeb B, Pajouhanfar S, Jazayeri A, Schoenberg E, Kumar G, Fortina P, Berger AC, Uitto J. Novel PTCH1 and concurrent TP53 mutations in four patients with numerous non-syndromic basal cell carcinomas: The paradigm of oncogenic synergy. Exp Dermatol 2021; 31:736-742. [PMID: 34862824 DOI: 10.1111/exd.14510] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 10/28/2021] [Accepted: 11/22/2021] [Indexed: 12/12/2022]
Abstract
There has been a significant increase in basal cell carcinoma (BCC) incidence, the most common cancer in humans and the age of presentation with the first diagnosis of BCC has decreased in past decades. In this study, we investigated the possibility of genetic markers that can lead to earlier and closer observation of patients at high risk for development of multiple BCCs. The overall goal is to decrease the morbidity and the economic burden of diagnosis and treatment of recurring and/or advanced BCCs. Four patients with numerous BCCs, some of them exceptionally large, were included in this study. A sample of representative BCCs, normal non-sun-exposed skin and blood samples were obtained from each patient. Whole-exome sequencing of DNA was conducted on all samples, and a series of bioinformatics filtering was performed to identify potentially pathogenic sequence variants. The analysis of the data resulted in detection of oncogenic mutations in PTCH1, two of which being novel, and concurrent mutations in TP53 in BCC tumours of all four patients. Such mutations may explain the numerous and postexcision recurring nature of the BCCs of exceptionally large size observed in all these patients, and they can be suggested to serve as a genetic marker for high-risk patients for early detection, prognostication and close follow-up.
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Affiliation(s)
- Bahar Dasgeb
- Department of Surgical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, USA
| | - Sara Pajouhanfar
- Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Ali Jazayeri
- College of Computing & Informatics, Drexel University, Philadelphia, Pennsylvania, USA
| | - Elizabeth Schoenberg
- Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Gaurav Kumar
- Cancer Genomics and Bioinformatics Laboratory, Sidney Kimmel Cancer Center, Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Paolo Fortina
- Cancer Genomics and Bioinformatics Laboratory, Sidney Kimmel Cancer Center, Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Adam C Berger
- Department of Surgical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, USA
| | - Jouni Uitto
- Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
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Rico-Leo EM, Lorenzo-Martín LF, Román ÁC, Bustelo XR, Merino JM, Fernández-Salguero PM. Aryl hydrocarbon receptor controls skin homeostasis, regeneration, and hair follicle cycling by adjusting epidermal stem cell function. Stem Cells 2021; 39:1733-1750. [PMID: 34423894 DOI: 10.1002/stem.3443] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Accepted: 07/28/2021] [Indexed: 12/20/2022]
Abstract
Skin integrity requires constant maintenance of a quiescent, yet responsive, population of stem cells. While interfollicular epidermal progenitors control normal homeostasis, hair follicle stem cells residing within the bulge provide regenerative potential during hair cycle and in response to wounding. The aryl hydrocarbon receptor (AhR) modulates cell plasticity and differentiation and its overactivation results in severe skin lesions in humans. However, its physiological role in skin homeostasis and hair growth is unknown. Reconstitution assays grafting primary keratinocytes and dermal fibroblasts into nude mice and 3-D epidermal equivalents revealed a positive role for AhR in skin regeneration, epidermal differentiation, and stem cell maintenance. Furthermore, lack of receptor expression in AhR-/- mice delayed morphogenesis and impaired hair regrowth with a phenotype closely correlating with a reduction in suprabasal bulge stem cells (α6low CD34+ ). Moreover, RNA-microarray and RT-qPCR analyses of fluorescence-activated cell sorting (FACS)-isolated bulge stem cells revealed that AhR depletion impaired transcriptional signatures typical of both epidermal progenitors and bulge stem cells but upregulated differentiation markers likely compromising their undifferentiated phenotype. Altogether, our findings support that AhR controls skin regeneration and homeostasis by ensuring epidermal stem cell identity and highlights this receptor as potential target for the treatment of cutaneous pathologies.
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Affiliation(s)
- Eva María Rico-Leo
- Departamento de Bioquímica y Biología Molecular y Genética, Facultad de Ciencias, Universidad de Extremadura, Badajoz, Spain.,Instituto Universitario de Investigación Biosanitaria de Extremadura (INUBE), Badajoz, Spain
| | | | - Ángel Carlos Román
- Departamento de Bioquímica y Biología Molecular y Genética, Facultad de Ciencias, Universidad de Extremadura, Badajoz, Spain
| | - Xosé Ramón Bustelo
- Centro de Investigación del Cáncer and CIBERONC, CSIC-Universidad de Salamanca, Salamanca, Spain
| | - Jaime María Merino
- Departamento de Bioquímica y Biología Molecular y Genética, Facultad de Ciencias, Universidad de Extremadura, Badajoz, Spain.,Instituto Universitario de Investigación Biosanitaria de Extremadura (INUBE), Badajoz, Spain
| | - Pedro María Fernández-Salguero
- Departamento de Bioquímica y Biología Molecular y Genética, Facultad de Ciencias, Universidad de Extremadura, Badajoz, Spain.,Instituto Universitario de Investigación Biosanitaria de Extremadura (INUBE), Badajoz, Spain
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44
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Seidl-Philipp M, Frischhut N, Höllweger N, Schmuth M, Nguyen VA. Known and new facts on basal cell carcinoma. J Dtsch Dermatol Ges 2021; 19:1021-1041. [PMID: 34288482 PMCID: PMC8361778 DOI: 10.1111/ddg.14580] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Accepted: 06/02/2021] [Indexed: 12/18/2022]
Abstract
Basal cell carcinoma (BCC) is the most common malignant tumor in light‐skinned people and amounts to about 75 % of all cases of skin cancer. Increasing incidence rates have been reported for decades all over the world. The main risk factors include UV radiation, male sex, light skin type, advanced age, long‐term immunosuppression, a positive individual or family history, and certain genodermatoses. BCC metastasizes only rarely, and its mortality is low, but it is associated with significant morbidity. Genetic mutations especially in the hedgehog pathway play an important role in BCC pathogenesis. Non‐invasive procedures such as optical coherence tomography or confocal laser scan microscopy are increasingly utilized for diagnostics in addition to visual inspection and dermatoscopy, but only in exceptional cases can histological confirmation of the diagnosis be dispensed with. Various clinical and histological subtypes have been defined. Differentiating between BCC with high and low risk of recurrence has a significant influence on the choice of treatment. Most BCC can be treated effectively and safely with standard surgery, or in selected cases with topical treatment. Locally advanced and metastasized BCC must be treated with radiation or systemic therapy. Radiation is also an option for older patients with contraindications for surgery. The hedgehog inhibitors vismodegib and sonidegib are currently approved for systemic therapy of BCC in Europe. Approval for the PD1 inhibitor cemiplimab as second‐line therapy is expected in the near future.
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Affiliation(s)
- Magdalena Seidl-Philipp
- University Hospital for Dermatology, Venereology, and Allergology, Medical University Innsbruck, Austria
| | - Nina Frischhut
- University Hospital for Dermatology, Venereology, and Allergology, Medical University Innsbruck, Austria
| | - Nicole Höllweger
- University Hospital for Dermatology, Venereology, and Allergology, Medical University Innsbruck, Austria
| | - Matthias Schmuth
- University Hospital for Dermatology, Venereology, and Allergology, Medical University Innsbruck, Austria
| | - Van Anh Nguyen
- University Hospital for Dermatology, Venereology, and Allergology, Medical University Innsbruck, Austria
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45
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Seidl-Philipp M, Frischhut N, Höllweger N, Schmuth M, Nguyen VA. Bekanntes und Neues zum Basalzellkarzinom. J Dtsch Dermatol Ges 2021; 19:1021-1043. [PMID: 34288462 DOI: 10.1111/ddg.14580_g] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Accepted: 06/02/2021] [Indexed: 11/27/2022]
Affiliation(s)
- Magdalena Seidl-Philipp
- Universitätsklinik für Dermatologie, Venerologie und Allergologie, Medizinische Universität Innsbruck, Österreich
| | - Nina Frischhut
- Universitätsklinik für Dermatologie, Venerologie und Allergologie, Medizinische Universität Innsbruck, Österreich
| | - Nicole Höllweger
- Universitätsklinik für Dermatologie, Venerologie und Allergologie, Medizinische Universität Innsbruck, Österreich
| | - Matthias Schmuth
- Universitätsklinik für Dermatologie, Venerologie und Allergologie, Medizinische Universität Innsbruck, Österreich
| | - Van Anh Nguyen
- Universitätsklinik für Dermatologie, Venerologie und Allergologie, Medizinische Universität Innsbruck, Österreich
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46
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Yuan Y, Salinas Parra N, Chen Q, Iglesias-Bartolome R. Oncogenic Hedgehog-smoothened signaling depends on YAP1-TAZ/TEAD transcription to restrain differentiation in basal cell carcinoma. J Invest Dermatol 2021; 142:65-76.e7. [PMID: 34293352 DOI: 10.1016/j.jid.2021.06.020] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 06/09/2021] [Accepted: 06/10/2021] [Indexed: 10/20/2022]
Abstract
Disruption of the transcriptional activity of the Hippo pathway members YAP1 and TAZ has become a major target for cancer treatment. However, detailed analysis of the effectivity and networks affected by YAP1/TAZ transcriptional targeting are limited. Here, we utilize TEADi, an inhibitor of the binding of YAP1 and TAZ with their main transcriptional target TEAD in a mouse model of basal cell carcinoma (BCC) to unveil the consequences of YAP1/TAZ transcriptional inhibition in cancer cells. Both TEADi and YAP1/TAZ knockdown lead to reduced proliferation and increased differentiation of mouse BCC driven by oncogenic Hedgehog-Smoothened (SmoM2) activity. While TEAD transcriptional networks were essential to inactivate differentiation in BCC, this inactivation was found to be indirect and potentially mediated through the repression of KLF4 by SNAI2. By comparing the transcriptional effects of TEADi with those caused by YAP1/TAZ depletion, we determined YAP1/TAZ TEAD-independent effects in cancer cells that impact STAT3 and NF-κB. Our results reveal the gene networks affected by targeting YAP1/TAZ-TEAD in BCC tumors and expose potential pitfalls for targeting TEAD transcription in cancer.
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Affiliation(s)
- Yao Yuan
- Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Natalia Salinas Parra
- Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Qianming Chen
- The Affiliated Stomatology Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Ramiro Iglesias-Bartolome
- Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
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47
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Khalaf K, Hana D, Chou JTT, Singh C, Mackiewicz A, Kaczmarek M. Aspects of the Tumor Microenvironment Involved in Immune Resistance and Drug Resistance. Front Immunol 2021; 12:656364. [PMID: 34122412 PMCID: PMC8190405 DOI: 10.3389/fimmu.2021.656364] [Citation(s) in RCA: 240] [Impact Index Per Article: 60.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Accepted: 04/27/2021] [Indexed: 12/11/2022] Open
Abstract
The tumor microenvironment (TME) is a complex and ever-changing "rogue organ" composed of its own blood supply, lymphatic and nervous systems, stroma, immune cells and extracellular matrix (ECM). These complex components, utilizing both benign and malignant cells, nurture the harsh, immunosuppressive and nutrient-deficient environment necessary for tumor cell growth, proliferation and phenotypic flexibility and variation. An important aspect of the TME is cellular crosstalk and cell-to-ECM communication. This interaction induces the release of soluble factors responsible for immune evasion and ECM remodeling, which further contribute to therapy resistance. Other aspects are the presence of exosomes contributed by both malignant and benign cells, circulating deregulated microRNAs and TME-specific metabolic patterns which further potentiate the progression and/or resistance to therapy. In addition to biochemical signaling, specific TME characteristics such as the hypoxic environment, metabolic derangements, and abnormal mechanical forces have been implicated in the development of treatment resistance. In this review, we will provide an overview of tumor microenvironmental composition, structure, and features that influence immune suppression and contribute to treatment resistance.
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Affiliation(s)
- Khalil Khalaf
- Department of Cancer Diagnostics and Immunology, Greater Poland Cancer Center, Poznań, Poland
- Department of Cancer Immunology, Poznan University of Medical Sciences, Poznań, Poland
| | - Doris Hana
- Department of Cancer Diagnostics and Immunology, Greater Poland Cancer Center, Poznań, Poland
- Department of Cancer Immunology, Poznan University of Medical Sciences, Poznań, Poland
| | - Jadzia Tin-Tsen Chou
- Department of Cancer Diagnostics and Immunology, Greater Poland Cancer Center, Poznań, Poland
- Department of Cancer Immunology, Poznan University of Medical Sciences, Poznań, Poland
| | - Chandpreet Singh
- Department of Cancer Diagnostics and Immunology, Greater Poland Cancer Center, Poznań, Poland
- Department of Cancer Immunology, Poznan University of Medical Sciences, Poznań, Poland
| | - Andrzej Mackiewicz
- Department of Cancer Diagnostics and Immunology, Greater Poland Cancer Center, Poznań, Poland
- Department of Cancer Immunology, Poznan University of Medical Sciences, Poznań, Poland
| | - Mariusz Kaczmarek
- Department of Cancer Diagnostics and Immunology, Greater Poland Cancer Center, Poznań, Poland
- Department of Cancer Immunology, Poznan University of Medical Sciences, Poznań, Poland
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48
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Rahman MM, Herath D, Bladen JC, Atkar R, Pirzado MS, Harwood C, Philpott MP, Neill GW. Differential expression of phosphorylated MEK and ERK correlates with aggressive BCC subtypes. Carcinogenesis 2021; 42:975-983. [PMID: 34003214 DOI: 10.1093/carcin/bgab036] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 04/29/2021] [Accepted: 05/17/2021] [Indexed: 11/14/2022] Open
Abstract
Basal cell carcinoma (BCC) is associated with aberrant Hedgehog (HH) signalling through mutational inactivation of PTCH1; however, there is conflicting data regarding MEK/ERK signalling in BCC and the signalling pathway interactions in these carcinomas. To address this, expression of active phospho (p) MEK and ERK was examined in a panel of 15 non-aggressive and 14 aggressive BCCs. Although not uniformly expressed, both phospho-proteins were detected in the nuclei and/or cytoplasm of normal and tumour-associated epidermal cells however, whereas phospho-MEK (pMEK) was present in all non-aggressive BCCs (14/14), phospho-ERK (pERK) was rarely expressed (2/14). In contrast pERK expression was more prevalent in aggressive tumours (11/14). Interestingly, pMEK was only localized to the tumour mass whereas pERK was expressed in tumours and stroma of aggressive BCCs. Similarly, pERK (but not pMEK) was absent in mouse BCC-like tumours derived from X-ray irradiated Ptch1+/- mice with stromal pERK observed in myofibroblasts of the aggressive variant as well as in the tumour mass. RNA sequencing analysis of tumour epithelium and stroma of aggressive and non-aggressive BCC revealed the upregulation of epidermal growth factor receptor- and ERK-related pathways. Angiogenesis and immune response pathways were also upregulated in the stroma compared with the tumour. PTCH1 suppressed NEB1 immortalized keratinocytes (shPTCH1) display upregulated pERK that can be independent of MEK expression. Furthermore, epidermal growth factor pathway inhibitors affect the HH pathway by suppressing GLI1. These studies reveal differential expression of pERK between human BCC subtypes that maybe active by a pathway independent of MEK.
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Affiliation(s)
- Muhammad M Rahman
- Centre for Cutaneous Research, Blizard Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, UK
| | - Dimalee Herath
- Centre for Cutaneous Research, Blizard Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, UK
| | - John C Bladen
- Centre for Cutaneous Research, Blizard Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, UK
| | - Ravinder Atkar
- Centre for Cutaneous Research, Blizard Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, UK
| | - Muhammad S Pirzado
- Centre for Cutaneous Research, Blizard Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, UK
| | - Catherine Harwood
- Centre for Cutaneous Research, Blizard Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, UK
| | - Michael P Philpott
- Centre for Cutaneous Research, Blizard Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, UK
| | - Graham W Neill
- Centre for Cutaneous Research, Blizard Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, UK
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49
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Villani A, Fabbrocini G, Costa C, Ocampo-Garza SS, Lallas A, Scalvenzi M. Expert opinion on sonidegib efficacy, safety and tolerability. Expert Opin Drug Saf 2021; 20:877-882. [PMID: 33888008 DOI: 10.1080/14740338.2021.1921734] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Introduction: Hedgehog inhibitors are an alternative treatment option for patients with advanced BCCs not eligible for standard therapies due to lack of efficacy, high recurrence risk, and high-rate morbidity. Sonidegib, an oral smoothened antagonist, has been approved for the treatment of adult patients with locally advanced basal cell carcinoma. Several studies and randomized controlled trials have been conducted in order to evaluate the efficacy, safety, and tolerability of this new molecule.Areas covered: The aim of this article is to provide a complete overview on the use of sonidegib for the treatment of advanced BCCs describing the efficacy, safety, and drug tolerability of this drug.Expert opinion: Sonidegib, with a different pharmacokinetics profile from that of the other SMO-inhibitor vismodegib, demonstrated to be an efficacious and well-tolerated treatment in patients with locally advanced BCC. Although several drug-related adverse events have already been described, different strategies should be taken into account to better manage this small molecule while avoiding treatment discontinuation. The use of sonidegib as neoadjuvant therapy or combined with other hedgehog pathway inhibitors targeting different sites and to date, only available for pre-clinical studies, should also be considered.
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Affiliation(s)
- Alessia Villani
- Dermatology Unit, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Gabriella Fabbrocini
- Dermatology Unit, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Claudia Costa
- Dermatology Unit, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Sonia Sofia Ocampo-Garza
- Dermatology Department, University Hospital ¨Dr. José Eleuterio González¨, Universidad Autónoma De Nuevo León, Monterrey, Mexico
| | - Aimilios Lallas
- First Department of Dermatology, Aristotle University, Thessaloniki, Greece
| | - Massimiliano Scalvenzi
- Dermatology Unit, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
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50
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Mancini M, Cappello A, Pecorari R, Lena AM, Montanaro M, Fania L, Ricci F, Di Lella G, Piro MC, Abeni D, Dellambra E, Mauriello A, Melino G, Candi E. Involvement of transcribed lncRNA uc.291 and SWI/SNF complex in cutaneous squamous cell carcinoma. Discov Oncol 2021; 12:14. [PMID: 35201472 PMCID: PMC8777507 DOI: 10.1007/s12672-021-00409-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 04/19/2021] [Indexed: 12/24/2022] Open
Abstract
While non-melanoma skin cancers (NMSCs) are the most common tumours in humans, only the sub-type cutaneous squamous cell carcinoma (cSCC), might become metastatic with high lethality. We have recently identified a regulatory pathway involving the lncRNA transcript uc.291 in controlling the expression of epidermal differentiation complex genes via the interaction with ACTL6A, a component of the chromatin remodelling complex SWI/SNF. Since transcribed ultra-conserved regions (T-UCRs) are expressed in normal tissues and are deregulated in tumorigenesis, here we hypothesize a potential role for dysregulation of this axis in cSCC, accounting for the de-differentiation process observed in aggressive poorly differentiated cutaneous carcinomas. We therefore analysed their expression patterns in human tumour biopsies at mRNA and protein levels. The results suggest that by altering chromatin accessibility of the epidermal differentiation complex genes, down-regulation of uc.291 and BRG1 expression contribute to the de-differentiation process seen in keratinocyte malignancy. This provides future direction for the identification of clinical biomarkers in cutaneous SCC. Analysis of publicly available data sets indicates that the above may also be a general feature for SCCs of different origins.
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Affiliation(s)
- M. Mancini
- Istituto Dermopatico Dell’Immacolata-IRCCS, via dei Monti di Creta 104, 00167 Rome, Italy
| | - A. Cappello
- Department of Experimental Medicine, University of Rome “Tor Vergata”, via Montpellier 1, 00133 Rome, Italy
| | - R. Pecorari
- Department of Experimental Medicine, University of Rome “Tor Vergata”, via Montpellier 1, 00133 Rome, Italy
| | - A. M. Lena
- Department of Experimental Medicine, University of Rome “Tor Vergata”, via Montpellier 1, 00133 Rome, Italy
| | - M. Montanaro
- Department of Experimental Medicine, University of Rome “Tor Vergata”, via Montpellier 1, 00133 Rome, Italy
| | - L. Fania
- Istituto Dermopatico Dell’Immacolata-IRCCS, via dei Monti di Creta 104, 00167 Rome, Italy
| | - F. Ricci
- Istituto Dermopatico Dell’Immacolata-IRCCS, via dei Monti di Creta 104, 00167 Rome, Italy
| | - G. Di Lella
- Istituto Dermopatico Dell’Immacolata-IRCCS, via dei Monti di Creta 104, 00167 Rome, Italy
| | - M. C. Piro
- Department of Experimental Medicine, University of Rome “Tor Vergata”, via Montpellier 1, 00133 Rome, Italy
| | - D. Abeni
- Istituto Dermopatico Dell’Immacolata-IRCCS, via dei Monti di Creta 104, 00167 Rome, Italy
| | - E. Dellambra
- Istituto Dermopatico Dell’Immacolata-IRCCS, via dei Monti di Creta 104, 00167 Rome, Italy
| | - A. Mauriello
- Department of Experimental Medicine, University of Rome “Tor Vergata”, via Montpellier 1, 00133 Rome, Italy
| | - G. Melino
- Department of Experimental Medicine, University of Rome “Tor Vergata”, via Montpellier 1, 00133 Rome, Italy
| | - E. Candi
- Istituto Dermopatico Dell’Immacolata-IRCCS, via dei Monti di Creta 104, 00167 Rome, Italy
- Department of Experimental Medicine, University of Rome “Tor Vergata”, via Montpellier 1, 00133 Rome, Italy
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