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1
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Mas-Ponte D, McCullough M, Supek F. Spectrum of DNA mismatch repair failures viewed through the lens of cancer genomics and implications for therapy. Clin Sci (Lond) 2022; 136:383-404. [PMID: 35274136 PMCID: PMC8919091 DOI: 10.1042/cs20210682] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 02/02/2022] [Accepted: 02/28/2022] [Indexed: 12/15/2022]
Abstract
Genome sequencing can be used to detect DNA repair failures in tumors and learn about underlying mechanisms. Here, we synthesize findings from genomic studies that examined deficiencies of the DNA mismatch repair (MMR) pathway. The impairment of MMR results in genome-wide hypermutation and in the 'microsatellite instability' (MSI) phenotype-occurrence of indel mutations at short tandem repeat (microsatellite) loci. The MSI status of tumors was traditionally assessed by molecular testing of a selected set of MS loci or by measuring MMR protein expression levels. Today, genomic data can provide a more complete picture of the consequences on genomic instability. Multiple computational studies examined somatic mutation distributions that result from failed DNA repair pathways in tumors. These include analyzing the commonly studied trinucleotide mutational spectra of single-nucleotide variants (SNVs), as well as of other features such as indels, structural variants, mutation clusters and regional mutation rate redistribution. The identified mutation patterns can be used to rigorously measure prevalence of MMR failures across cancer types, and potentially to subcategorize the MMR deficiencies. Diverse data sources, genomic and pre-genomic, from human and from experimental models, suggest there are different ways in which MMR can fail, and/or that the cell-type or genetic background may result in different types of MMR mutational patterns. The spectrum of MMR failures may direct cancer evolution, generating particular sets of driver mutations. Moreover, MMR affects outcomes of therapy by DNA damaging drugs, antimetabolites, nonsense-mediated mRNA decay (NMD) inhibitors, and immunotherapy by promoting either resistance or sensitivity, depending on the type of therapy.
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Affiliation(s)
- David Mas-Ponte
- Genome Data Science, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute for Science and Technology, Baldiri Reixac 10, Barcelona 08028, Spain
| | - Marcel McCullough
- Genome Data Science, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute for Science and Technology, Baldiri Reixac 10, Barcelona 08028, Spain
| | - Fran Supek
- Genome Data Science, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute for Science and Technology, Baldiri Reixac 10, Barcelona 08028, Spain
- Catalan Institution for Research and Advanced Studies (ICREA), Pg Lluís Companys, 23, Barcelona 08010, Spain
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2
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Fakhri S, Zachariah Moradi S, DeLiberto LK, Bishayee A. Cellular senescence signaling in cancer: A novel therapeutic target to combat human malignancies. Biochem Pharmacol 2022; 199:114989. [DOI: 10.1016/j.bcp.2022.114989] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 03/05/2022] [Accepted: 03/07/2022] [Indexed: 12/26/2022]
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Zhou F, Aipire A, Xia L, Halike X, Yuan P, Sulayman M, Wang W, Li J. Marchantia polymorpha L. ethanol extract induces apoptosis in hepatocellular carcinoma cells via intrinsic- and endoplasmic reticulum stress-associated pathways. Chin Med 2021; 16:94. [PMID: 34583719 PMCID: PMC8477563 DOI: 10.1186/s13020-021-00504-4] [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: 07/11/2021] [Accepted: 09/12/2021] [Indexed: 12/24/2022] Open
Abstract
Background Marchantia polymorpha L. is a kind of Chinese herbal medicine and has various biological activities including antioxidant and antifungal. However, it is not clear about the antitumor effect and mechanism of M. polymorpha. We prepared M. polymorpha ethanol extract (MPEE) and investigated its antitumor effect on hepatocellular carcinoma cells both in vitro and in vivo. Methods The viability of hepatocellular carcinoma cells was detected by MTT assay. The distribution of cell cycle was analyzed by propidium iodide (PI) staining. The morphology of nuclei was observed by Hoechst 33258 staining. Apoptosis was detected by Annexin V/PI staining. JC-1 fluorescent probe and DCFH-DA were used to detect the mitochondrial membrane potential (ΔψM) and the level of reactive oxygen species (ROS), respectively. Caspase inhibitors were used to test the function of caspase in the induction of apoptosis. Quantitative real time polymerase chain reaction (qRT-PCR) and Western blot were used to evaluate the levels of mRNA and protein, respectively. Differentially expressed genes and signaling pathways were identified by transcriptome analysis. The H22 tumor mouse model was used to detect the antitumor effect of the extract. Results MPEE significantly suppressed the migration and growth of BEL-7404, HepG2 and H22 cells in a dose- and time-dependent manner through induction of apoptosis characterized by chromosomal condensation and cell cycle arrest at G0/G1 and G2/M phases. MPEE induced mitochondria-dependent apoptosis via upregulation of Bax and downregulation of Bcl-2 to reduce mitochondrial membrane potential and increase the release of cytochrome c. The levels of cleaved caspase-8 and -9 were significantly increased, which sequentially activated caspase-3 to cleave PARP. We further found that MPEE significantly increased ROS production and activated endoplasmic reticulum (ER) stress associated-apoptotic signaling pathway. Moreover, MPEE significantly inhibited H22 tumor growth in mouse model and improved the survival of tumor mice. Conclusion These results suggested that MPEE suppressed hepatocellular carcinoma cell growth through induction of apoptosis via intrinsic- and ER stress-associated pathways. Supplementary Information The online version contains supplementary material available at 10.1186/s13020-021-00504-4.
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Affiliation(s)
- Fangfang Zhou
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi, 830046, China
| | - Adila Aipire
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi, 830046, China
| | - Lijie Xia
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi, 830046, China
| | - Xierenguli Halike
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi, 830046, China
| | - Pengfei Yuan
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi, 830046, China
| | - Mamtimin Sulayman
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi, 830046, China
| | - Weilan Wang
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi, 830046, China.
| | - Jinyao Li
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi, 830046, China.
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Estupiñán Ó, Niza E, Bravo I, Rey V, Tornín J, Gallego B, Clemente-Casares P, Moris F, Ocaña A, Blanco-Lorenzo V, Rodríguez-Santamaría M, Vallina-Álvarez A, González MV, Rodríguez A, Hermida-Merino D, Alonso-Moreno C, Rodríguez R. Mithramycin delivery systems to develop effective therapies in sarcomas. J Nanobiotechnology 2021; 19:267. [PMID: 34488783 PMCID: PMC8419920 DOI: 10.1186/s12951-021-01008-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Accepted: 08/20/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Sarcomas comprise a group of aggressive malignancies with very little treatment options beyond standard chemotherapy. Reposition of approved drugs represents an attractive approach to identify effective therapeutic compounds. One example is mithramycin (MTM), a natural antibiotic which has demonstrated a strong antitumour activity in several tumour types, including sarcomas. However, its widespread use in the clinic was limited by its poor toxicity profile. RESULTS In order to improve the therapeutic index of MTM, we have loaded MTM into newly developed nanocarrier formulations. First, polylactide (PLA) polymeric nanoparticles (NPs) were generated by nanoprecipitation. Also, liposomes (LIP) were prepared by ethanol injection and evaporation solvent method. Finally, MTM-loaded hydrogels (HG) were obtained by passive loading using a urea derivative non-peptidic hydrogelator. MTM-loaded NPs and LIP display optimal hydrodynamic radii between 80 and 105 nm with a very low polydispersity index (PdI) and encapsulation efficiencies (EE) of 92 and 30%, respectively. All formulations show a high stability and different release rates ranging from a fast release in HG (100% after 30 min) to more sustained release from NPs (100% after 24 h) and LIP (40% after 48 h). In vitro assays confirmed that all assayed MTM formulations retain the cytotoxic, anti-invasive and anti-stemness potential of free MTM in models of myxoid liposarcoma, undifferentiated pleomorphic sarcoma and chondrosarcoma. In addition, whole genome transcriptomic analysis evidenced the ability of MTM, both free and encapsulated, to act as a multi-repressor of several tumour-promoting pathways at once. Importantly, the treatment of mice bearing sarcoma xenografts showed that encapsulated MTM exhibited enhanced therapeutic effects and was better tolerated than free MTM. CONCLUSIONS Overall, these novel formulations may represent an efficient and safer MTM-delivering alternative for sarcoma treatment.
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Affiliation(s)
- Óscar Estupiñán
- Sarcomas and Experimental Therapeutics Laboratory, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Hospital Universitario Central de Asturias, Avenida de Roma, s/n, 33011, Oviedo, Spain.,Instituto Universitario de Oncología del Principado de Asturias, 33011, Oviedo, Spain.,CIBER en Oncología (CIBERONC), 28029, Madrid, Spain
| | - Enrique Niza
- Centro Regional de Investigaciones Biomédicas, Unidad NanoCRIB, 02008, Albacete, Spain.,Universidad de Castilla-La Mancha, Facultad de Farmacia de Albacete, 02008, Albacete, Spain
| | - Iván Bravo
- Centro Regional de Investigaciones Biomédicas, Unidad NanoCRIB, 02008, Albacete, Spain.,Universidad de Castilla-La Mancha, Facultad de Farmacia de Albacete, 02008, Albacete, Spain
| | - Verónica Rey
- Sarcomas and Experimental Therapeutics Laboratory, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Hospital Universitario Central de Asturias, Avenida de Roma, s/n, 33011, Oviedo, Spain.,Instituto Universitario de Oncología del Principado de Asturias, 33011, Oviedo, Spain
| | - Juan Tornín
- Sarcomas and Experimental Therapeutics Laboratory, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Hospital Universitario Central de Asturias, Avenida de Roma, s/n, 33011, Oviedo, Spain.,Instituto Universitario de Oncología del Principado de Asturias, 33011, Oviedo, Spain.,Materials Science and Engineering Department, Universitat Politècnica de Catalunya (UPC), Escola d'Enginyeria Barcelona Est (EEBE), 08019, Barcelona, Spain.,Institut de Recerca Sant Joan de Déu, 08034, Barcelona, Spain
| | - Borja Gallego
- Sarcomas and Experimental Therapeutics Laboratory, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Hospital Universitario Central de Asturias, Avenida de Roma, s/n, 33011, Oviedo, Spain
| | - Pilar Clemente-Casares
- Universidad de Castilla-La Mancha, Facultad de Farmacia de Albacete, 02008, Albacete, Spain.,Centro Regional de Investigaciones Biomédicas (CRIB), UCLM, 02008, Albacete, Spain
| | | | - Alberto Ocaña
- CIBER en Oncología (CIBERONC), 28029, Madrid, Spain.,Experimental Therapeutics Unit, Hospital Clínico San Carlos, IdISSC, 28040, Madrid, Spain
| | - Verónica Blanco-Lorenzo
- Sarcomas and Experimental Therapeutics Laboratory, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Hospital Universitario Central de Asturias, Avenida de Roma, s/n, 33011, Oviedo, Spain.,Servicio de Anatomía Patológica, Hospital Universitario Central de Asturias, 33011, Oviedo, Spain
| | - Mar Rodríguez-Santamaría
- Sarcomas and Experimental Therapeutics Laboratory, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Hospital Universitario Central de Asturias, Avenida de Roma, s/n, 33011, Oviedo, Spain
| | - Aitana Vallina-Álvarez
- Instituto Universitario de Oncología del Principado de Asturias, 33011, Oviedo, Spain.,Servicio de Anatomía Patológica, Hospital Universitario Central de Asturias, 33011, Oviedo, Spain
| | - M Victoria González
- Sarcomas and Experimental Therapeutics Laboratory, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Hospital Universitario Central de Asturias, Avenida de Roma, s/n, 33011, Oviedo, Spain.,Instituto Universitario de Oncología del Principado de Asturias, 33011, Oviedo, Spain.,CIBER en Oncología (CIBERONC), 28029, Madrid, Spain.,Departamento de Cirugía, Universidad de Oviedo, 33006, Oviedo, Spain
| | - Aida Rodríguez
- Sarcomas and Experimental Therapeutics Laboratory, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Hospital Universitario Central de Asturias, Avenida de Roma, s/n, 33011, Oviedo, Spain
| | - Daniel Hermida-Merino
- Netherlands Organisation for Scientific Research (NWO), DUBBLE@ESRF, 38000, Grenoble, France
| | - Carlos Alonso-Moreno
- Centro Regional de Investigaciones Biomédicas, Unidad NanoCRIB, 02008, Albacete, Spain. .,Universidad de Castilla-La Mancha, Facultad de Farmacia de Albacete, 02008, Albacete, Spain.
| | - René Rodríguez
- Sarcomas and Experimental Therapeutics Laboratory, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Hospital Universitario Central de Asturias, Avenida de Roma, s/n, 33011, Oviedo, Spain. .,Instituto Universitario de Oncología del Principado de Asturias, 33011, Oviedo, Spain. .,CIBER en Oncología (CIBERONC), 28029, Madrid, Spain.
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Wensink E, Bond M, Kucukkose E, May A, Vink G, Koopman M, Kranenburg O, Roodhart J. A review of the sensitivity of metastatic colorectal cancer patients with deficient mismatch repair to standard-of-care chemotherapy and monoclonal antibodies, with recommendations for future research. Cancer Treat Rev 2021; 95:102174. [PMID: 33721596 DOI: 10.1016/j.ctrv.2021.102174] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 02/17/2021] [Accepted: 02/19/2021] [Indexed: 12/29/2022]
Abstract
In 5% of metastatic colorectal cancer (mCRC) patients, tumours display a deficient mismatch repair (dMMR) system. Immunotherapy is beneficial in dMMR mCRC patients and has recently been approved by the Food and Drug Administration for patients with unresectable or metastatic dMMR CRC. Although dMMR and proficient MMR (pMMR) CRC tumours are biologically distinct, they are commonly treated with the same chemotherapy and monoclonal antibodies. This includes dMMR mCRC patients who did not respond to immunotherapy (20-30%). However, it is unclear if these treatments are equally beneficial in dMMR mCRC. Of note, dMMR mCRC patients have a worse prognosis compared to pMMR, which may in part be caused by a lower response to treatment. To avoid unnecessary exposure to ineffective treatments and their associated toxicity, it is important to identify which systemic treatments are most beneficial in dMMR mCRC patients, thus improving their outcome. Indeed, future treatment strategies are likely to involve combinations of immunotherapy, chemotherapy and monoclonal antibodies. In this evidence-based review, we summarize clinical trials reporting treatment efficacy of different types of chemotherapy and monoclonal antibodies in dMMR mCRC patients. We also review the biological rationale behind a potential differential benefit of chemotherapy with or without monoclonal antibodies in dMMR mCRC patients. A barrier in the interpretation of preclinical results is the choice of model systems. They largely comprise traditional models, including cell lines and xenografts, rather than more representative models, such as patient-derived organoids. We provide concrete recommendations for clinical investigators and fundamental researchers to accelerate research regarding which systemic therapy is most effective in dMMR mCRC patients.
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Affiliation(s)
- Emerens Wensink
- Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584CX Utrecht, the Netherlands
| | - Marinde Bond
- Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584CX Utrecht, the Netherlands; Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Universiteitsweg 100, 3584CX Utrecht, the Netherlands
| | - Emre Kucukkose
- Department of Surgical Oncology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584CX Utrecht, the Netherlands
| | - Anne May
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Universiteitsweg 100, 3584CX Utrecht, the Netherlands
| | - Geraldine Vink
- Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584CX Utrecht, the Netherlands; Department of Research and Development, Netherlands Comprehensive Cancer Organisation, Godebaldkwartier 419, 3511DT Utrecht, the Netherlands
| | - Miriam Koopman
- Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584CX Utrecht, the Netherlands
| | - Onno Kranenburg
- Department of Surgical Oncology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584CX Utrecht, the Netherlands; Utrecht Platform for Organoid Technology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584CX Utrecht, the Netherlands
| | - Jeanine Roodhart
- Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584CX Utrecht, the Netherlands.
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Dubey AP, Vishwanath S, Nikhil P, Rathore A, Pathak A, Kumar R. Microsatellite Instability in Stage II and III Colorectal Cancer: Patterns and Profile. Indian J Med Paediatr Oncol 2018. [DOI: 10.4103/ijmpo.ijmpo_35_17] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Abstract
Introduction: Around 80% of colorectal carcinoma are associated with chromosomal instability while rest of 20% are euploid, possessing defect in mismatch repair system (MMR) quintessential for surveillance and correction of errors introduced into microsatellites. The microsatellite instability (MSI) phenotype has three major clinical applications: prognosis of colorectal cancer (CRC), prediction of response to 5 fluorouracil, and irinotecan, and genetic assessment of Lynch syndrome. Materials and Methods: We analyzed all Stage II and Stage III colorectal cancer (CRC) for MSI, who presented at Army Hospital, Research and Referral, New Delhi, from January 2014 to December 2016. Although patients of Stage II CRC were taken throughout the study period, Stage III CRC was included in last 1½ years to compare the prevalence of MSI in these two subsets of patients. Results: 26.2% of Stage II and 11.3% of Stage III patients were found to be MSI-high (MSI-H) (P = 0.04). Nineteen (86%) of 22 MSI-H patients were below 30 years of age (P = 0.01). Of 22 MSI-H patients, 18 had right-sided tumors (P = 0.03) and only three patients had rectal tumors. Most common pattern of MSI-H tumors was loss of expression of MLH1 and PMS2, seen in 15 of 16 (88%) of Stage II and three of 6 (50%) of Stage III CRC (P = 0.04). Conclusion: We conclude higher prevalence of MSI-H tumors in Stage II, as compared to Stage III CRC, which was demonstrated slightly higher in our study compared to published literature. MSI-H tumors tend to occur with high frequency in younger population, with right-sided colonic tumors, histopathology characterized by mucinous subtype with high prevalence of tumor infiltrating lymphocytes. Loss of expression of two MMR proteins, namely, PMS2 and MLH1 has been identified in most of MSI-H patients of our study, of which 86% were <30 years of age. This is in contrast to observation in previous studies where loss of PMS2 and MLH1 proteins was observed in older (>70 years) patients with MSI-H tumors, and in younger patients, MSI-H status was associated with loss of MLH1, MSH2, and MSH6.
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Affiliation(s)
- A P Dubey
- Department of Medical Oncology, Army Hospital Research and Referral, New Delhi, India
| | - S Vishwanath
- Department of Medical Oncology, Army Hospital Research and Referral, New Delhi, India
| | - P Nikhil
- Department of Medical Oncology, Army Hospital Research and Referral, New Delhi, India
| | - Anvesh Rathore
- Department of Medical Oncology, Army Hospital Research and Referral, New Delhi, India
| | - Abhishek Pathak
- Department of Medical Oncology, Army Hospital Research and Referral, New Delhi, India
| | - Rakesh Kumar
- Department of Radiodiagnosis, Army Hospital Research and Referral, New Delhi, India
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7
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Early Postoperative Low Expression of RAD50 in Rectal Cancer Patients Associates with Disease-Free Survival. Cancers (Basel) 2017; 9:cancers9120163. [PMID: 29189711 PMCID: PMC5742811 DOI: 10.3390/cancers9120163] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2017] [Revised: 11/24/2017] [Accepted: 11/27/2017] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Molecular biomarkers have the potential to predict response to the treatment of rectal cancer. In this study, we aimed to evaluate the prognostic and clinicopathological implication of RAD50 (DNA repair protein RAD50 homolog) expression in rectal cancer. METHODS A total of 266 rectal cancer patients who underwent surgery and received chemo- and radiotherapy between 2000 and 2011 were involved in the study. Postoperative RAD50 expression was determined by immunohistochemistry in surgical samples (n = 266). RESULTS Using Kaplan-Meier survival analysis, we found that low RAD50 expression in postoperative samples was associated with worse disease free survival (p = 0.001) and overall survival (p < 0.001) in early stage/low-grade tumors. In a comparison of patients with low vs. high RAD50 expression, we found that low levels of postoperative RAD50 expression in rectal cancer tissues were significantly associated with perineural invasion (p = 0.002). CONCLUSION Expression of RAD50 in rectal cancer may serve as a prognostic biomarker for long-term survival of patients with perineural invasion-positive tumors and for potential use in early stage and low-grade rectal cancer assessment.
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8
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Nicholson J, Jevons SJ, Groselj B, Ellermann S, Konietzny R, Kerr M, Kessler BM, Kiltie AE. E3 Ligase cIAP2 Mediates Downregulation of MRE11 and Radiosensitization in Response to HDAC Inhibition in Bladder Cancer. Cancer Res 2017; 77:3027-3039. [PMID: 28363998 DOI: 10.1158/0008-5472.can-16-3232] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Revised: 01/10/2017] [Accepted: 03/27/2017] [Indexed: 11/16/2022]
Abstract
The MRE11/RAD50/NBS1 (MRN) complex mediates DNA repair pathways, including double-strand breaks induced by radiotherapy. Meiotic recombination 11 homolog (MRE11) is downregulated by histone deacetylase inhibition (HDACi), resulting in reduced levels of DNA repair in bladder cancer cells and radiosensitization. In this study, we show that the mechanism of this downregulation is posttranslational and identify a C-terminally truncated MRE11, which is formed after HDAC inhibition as full-length MRE11 is downregulated. Truncated MRE11 was stabilized by proteasome inhibition, exhibited a decreased half-life after treatment with panobinostat, and therefore represents a newly identified intermediate induced and degraded in response to HDAC inhibition. The E3 ligase cellular inhibitor of apoptosis protein 2 (cIAP2) was upregulated in response to HDAC inhibition and was validated as a new MRE11 binding partner whose upregulation had similar effects to HDAC inhibition. cIAP2 overexpression resulted in downregulation and altered ubiquitination patterns of MRE11 and mediated radiosensitization in response to HDAC inhibition. These results highlight cIAP2 as a player in the DNA damage response as a posttranscriptional regulator of MRE11 and identify cIAP2 as a potential target for biomarker discovery or chemoradiation strategies in bladder cancer. Cancer Res; 77(11); 3027-39. ©2017 AACR.
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Affiliation(s)
- Judith Nicholson
- CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, United Kingdom.
| | - Sarah J Jevons
- CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, United Kingdom
| | - Blaz Groselj
- CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, United Kingdom
| | - Sophie Ellermann
- CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, United Kingdom
| | - Rebecca Konietzny
- TDI Mass Spectrometry Laboratory, Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Martin Kerr
- CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, United Kingdom
| | - Benedikt M Kessler
- TDI Mass Spectrometry Laboratory, Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Anne E Kiltie
- CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, United Kingdom.
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9
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Martinez-Cruzado L, Tornin J, Rodriguez A, Santos L, Allonca E, Fernandez-Garcia MT, Astudillo A, Garcia-Pedrero JM, Rodriguez R. Trabectedin and Campthotecin Synergistically Eliminate Cancer Stem Cells in Cell-of-Origin Sarcoma Models. Neoplasia 2017; 19:460-470. [PMID: 28494349 PMCID: PMC5421973 DOI: 10.1016/j.neo.2017.03.004] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2017] [Revised: 03/21/2017] [Accepted: 03/24/2017] [Indexed: 12/16/2022] Open
Abstract
Trabectedin has been approved for second-line treatment of soft tissue sarcomas. However, its efficacy to target sarcoma initiating cells has not been addressed yet. Here, we used pioneer models of myxoid/round cell liposarcoma (MRCLS) and undifferentiated pleomorphic sarcoma (UPS) developed from transformed human mesenchymal stromal/stem cells (MSCs) to evaluate the effect of trabectedin in the cell type responsible for initiating sarcomagenesis and their derived cancer stem cells (CSC) subpopulations. We found that low nanomolar concentrations of trabectedin efficiently inhibited the growth of sarcoma-initiating cells, induced cell cycle arrest, DNA damage and apoptosis. Interestingly, trabectedin treatment repressed the expression of multiple genes responsible for the development of the CSC phenotype, including pluripotency factors, CSC markers and related signaling pathways. Accordingly, trabectedin induced apoptosis and reduced the survival of CSC-enriched tumorsphere cultures with the same efficiency that inhibits the growth of bulk tumor population. In vivo, trabectedin significantly reduced the mitotic index of MRCLS xenografts and inhibited tumor growth at a similar extent to that observed in doxorubicin-treated tumors. Combination of trabectedin with campthotecin (CPT), a chemotherapeutic drug that shows a robust anti-tumor activity when combined with alkylating agents, resulted in a very strong synergistic inhibition of tumor cell growth and highly increased DNA damage and apoptosis induction. Importantly, the enhanced anti-tumor activity of this combination was also observed in CSC subpopulations. These data suggest that trabectedin and CPT combination may constitute a novel strategy to effectively target both the cell-of-origin and CSC subpopulations in sarcoma.
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Affiliation(s)
- Lucia Martinez-Cruzado
- Hospital Universitario Central de Asturias - Instituto de Investigación Sanitaria del Principado de Asturias, Oviedo, Asturias; Instituto Universitario de Oncología del Principado de Asturias, Oviedo, Spain
| | - Juan Tornin
- Hospital Universitario Central de Asturias - Instituto de Investigación Sanitaria del Principado de Asturias, Oviedo, Asturias; Instituto Universitario de Oncología del Principado de Asturias, Oviedo, Spain
| | - Aida Rodriguez
- Hospital Universitario Central de Asturias - Instituto de Investigación Sanitaria del Principado de Asturias, Oviedo, Asturias
| | - Laura Santos
- Hospital Universitario Central de Asturias - Instituto de Investigación Sanitaria del Principado de Asturias, Oviedo, Asturias
| | - Eva Allonca
- Hospital Universitario Central de Asturias - Instituto de Investigación Sanitaria del Principado de Asturias, Oviedo, Asturias; Instituto Universitario de Oncología del Principado de Asturias, Oviedo, Spain
| | | | - Aurora Astudillo
- Servicio de Anatomía Patológica, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - Juana Maria Garcia-Pedrero
- Hospital Universitario Central de Asturias - Instituto de Investigación Sanitaria del Principado de Asturias, Oviedo, Asturias; Instituto Universitario de Oncología del Principado de Asturias, Oviedo, Spain; CIBER en oncología (CIBERONC), Madrid, Spain
| | - Rene Rodriguez
- Hospital Universitario Central de Asturias - Instituto de Investigación Sanitaria del Principado de Asturias, Oviedo, Asturias; Instituto Universitario de Oncología del Principado de Asturias, Oviedo, Spain; CIBER en oncología (CIBERONC), Madrid, Spain.
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Schizosaccharomyces pombe MutSα and MutLα Maintain Stability of Tetra-Nucleotide Repeats and Msh3 of Hepta-Nucleotide Repeats. G3-GENES GENOMES GENETICS 2017; 7:1463-1473. [PMID: 28341698 PMCID: PMC5427490 DOI: 10.1534/g3.117.040816] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Defective mismatch repair (MMR) in humans is associated with colon cancer and instability of microsatellites, that is, DNA sequences with one or several nucleotides repeated. Key factors of eukaryotic MMR are the heterodimers MutSα (Msh2-Msh6), which recognizes base-base mismatches and unpaired nucleotides in DNA, and MutLα (Mlh1-Pms1), which facilitates downstream steps. In addition, MutSβ (Msh2-Msh3) recognizes DNA loops of various sizes, although our previous data and the data presented here suggest that Msh3 of Schizosaccharomyces pombe does not play a role in MMR. To test microsatellite stability in S. pombe and hence DNA loop repair, we have inserted tetra-, penta-, and hepta-nucleotide repeats in the ade6 gene and determined their Ade+ reversion rates and spectra in wild type and various mutants. Our data indicate that loops with four unpaired nucleotides in the nascent and the template strand are the upper limit of MutSα- and MutLα-mediated MMR in S. pombe Stability of hepta-nucleotide repeats requires Msh3 and Exo1 in MMR-independent processes as well as the DNA repair proteins Rad50, Rad51, and Rad2FEN1 Most strikingly, mutation rates in the double mutants msh3 exo1 and msh3 rad51 were decreased when compared to respective single mutants, indicating that Msh3 prevents error prone processes carried out by Exo1 and Rad51. We conclude that Msh3 has no obvious function in MMR in S. pombe, but contributes to DNA repeat stability in MMR-independent processes.
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Tornin J, Martinez-Cruzado L, Santos L, Rodriguez A, Núñez LE, Oro P, Hermosilla MA, Allonca E, Fernández-García MT, Astudillo A, Suarez C, Morís F, Rodriguez R. Inhibition of SP1 by the mithramycin analog EC-8042 efficiently targets tumor initiating cells in sarcoma. Oncotarget 2016; 7:30935-50. [PMID: 27105533 PMCID: PMC5058729 DOI: 10.18632/oncotarget.8817] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2015] [Accepted: 03/28/2016] [Indexed: 12/13/2022] Open
Abstract
Tumor initiating cells (TICs), responsible for tumor initiation, and cancer stem cells (CSCs), responsible for tumor expansion and propagation, are often resistant to chemotherapeutic agents. To find therapeutic targets against sarcoma initiating and propagating cells we used models of myxoid liposarcoma (MLS) and undifferentiated pleomorphic sarcoma (UPS) developed from human mesenchymal stromal/stem cells (hMSCs), which constitute the most likely cell-of-origin for sarcoma. We found that SP1-mediated transcription was among the most significantly altered signaling. To inhibit SP1 activity, we used EC-8042, a mithramycin (MTM) analog (mithralog) with enhanced anti-tumor activity and highly improved safety. EC-8042 inhibited the growth of TIC cultures, induced cell cycle arrest and apoptosis and upregulated the adipogenic factor CEBPα. SP1 knockdown was able to mimic the anti-proliferative effects induced by EC-8042. Importantly, EC-8042 was not recognized as a substrate by several ABC efflux pumps involved in drug resistance, and, opposite to the chemotherapeutic drug doxorubicin, repressed the expression of many genes responsible for the TIC/CSC phenotype, including SOX2, C-MYC, NOTCH1 and NFκB1. Accordingly, EC-8042, but not doxorubicin, efficiently reduced the survival of CSC-enriched tumorsphere sarcoma cultures. In vivo, EC-8042 induced a profound inhibition of tumor growth associated to a strong reduction of the mitotic index and the induction of adipogenic differentiation and senescence. Finally, EC-8042 reduced the ability of tumor cells to reinitiate tumor growth. These data suggest that EC-8042 could constitute an effective treatment against both TIC and CSC subpopulations in sarcoma.
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Affiliation(s)
- Juan Tornin
- Hospital Universitario Central de Asturias and Instituto Universitario de Oncología del Principado de Asturias, Oviedo, Spain
| | - Lucia Martinez-Cruzado
- Hospital Universitario Central de Asturias and Instituto Universitario de Oncología del Principado de Asturias, Oviedo, Spain
| | - Laura Santos
- Hospital Universitario Central de Asturias and Instituto Universitario de Oncología del Principado de Asturias, Oviedo, Spain
| | - Aida Rodriguez
- Hospital Universitario Central de Asturias and Instituto Universitario de Oncología del Principado de Asturias, Oviedo, Spain
| | | | | | | | - Eva Allonca
- Hospital Universitario Central de Asturias and Instituto Universitario de Oncología del Principado de Asturias, Oviedo, Spain
| | | | - Aurora Astudillo
- Servicio de Anatomía Patológica, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - Carlos Suarez
- Hospital Universitario Central de Asturias and Instituto Universitario de Oncología del Principado de Asturias, Oviedo, Spain
| | | | - Rene Rodriguez
- Hospital Universitario Central de Asturias and Instituto Universitario de Oncología del Principado de Asturias, Oviedo, Spain
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12
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Stadler ZK. Diagnosis and management of DNA mismatch repair-deficient colorectal cancer. Hematol Oncol Clin North Am 2015; 29:29-41. [PMID: 25475571 DOI: 10.1016/j.hoc.2014.09.008] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
Colorectal tumors exhibiting defective DNA mismatch repair (MMR-D)/microsatellite instability (MSI-H) form a distinct subgroup of CRCs associated with important clinical and pathologic features. The identification of MMR-D/MSI-H may impact CRC prognosis, prediction of response to chemotherapeutic agents, and may necessitate the need for genetic assessment for Lynch syndrome. Oncologists remain at the forefront of diagnosing, treating, and managing patients with MMR-D/MSI-H CRC and ensuring that the clinical care of these patients reflect our evolving understanding of this unique CRC subtype.
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Affiliation(s)
- Zsofia K Stadler
- Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
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13
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Xu Y, Her C. Inhibition of Topoisomerase (DNA) I (TOP1): DNA Damage Repair and Anticancer Therapy. Biomolecules 2015; 5:1652-70. [PMID: 26287259 PMCID: PMC4598769 DOI: 10.3390/biom5031652] [Citation(s) in RCA: 98] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2015] [Accepted: 07/14/2015] [Indexed: 12/31/2022] Open
Abstract
Most chemotherapy regimens contain at least one DNA-damaging agent that preferentially affects the growth of cancer cells. This strategy takes advantage of the differences in cell proliferation between normal and cancer cells. Chemotherapeutic drugs are usually designed to target rapid-dividing cells because sustained proliferation is a common feature of cancer [1,2]. Rapid DNA replication is essential for highly proliferative cells, thus blocking of DNA replication will create numerous mutations and/or chromosome rearrangements—ultimately triggering cell death [3]. Along these lines, DNA topoisomerase inhibitors are of great interest because they help to maintain strand breaks generated by topoisomerases during replication. In this article, we discuss the characteristics of topoisomerase (DNA) I (TOP1) and its inhibitors, as well as the underlying DNA repair pathways and the use of TOP1 inhibitors in cancer therapy.
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Affiliation(s)
- Yang Xu
- School of Molecular Biosciences, College of Veterinary Medicine, Washington State University, Mail Drop 64-7520, Pullman, WA 99164, USA.
| | - Chengtao Her
- School of Molecular Biosciences, College of Veterinary Medicine, Washington State University, Mail Drop 64-7520, Pullman, WA 99164, USA.
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14
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EMAST is a Form of Microsatellite Instability That is Initiated by Inflammation and Modulates Colorectal Cancer Progression. Genes (Basel) 2015; 6:185-205. [PMID: 25836926 PMCID: PMC4488660 DOI: 10.3390/genes6020185] [Citation(s) in RCA: 74] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2015] [Revised: 03/19/2015] [Accepted: 03/23/2015] [Indexed: 12/12/2022] Open
Abstract
DNA mismatch repair (MMR) function is critical for correcting errors coincident with polymerase-driven DNA replication, and its proteins are frequent targets for inactivation (germline or somatic), generating a hypermutable tumor that drives cancer progression. The biomarker for defective DNA MMR is microsatellite instability-high (MSI-H), observed in ~15% of colorectal cancers, and defined by mono- and dinucleotide microsatellite frameshift mutations. MSI-H is highly correlated with loss of MMR protein expression, is commonly diploid, is often located in the right side of the colon, prognosticates good patient outcome, and predicts poor efficacy with 5-fluorouracil treatment. Elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) is another form of MSI at tetranucleotide repeats that has been observed in multiple cancers, but its etiology and clinical relevance to patient care has only been recently illuminated. Specifically, EMAST is an acquired somatic defect observed in up to 60% of colorectal cancers and caused by unique dysfunction of the DNA MMR protein MSH3 (and its DNA MMR complex MutSβ, a heterodimer of MSH2-MSH3), and in particular a loss-of-function phenotype due to a reversible shift from its normal nuclear location into the cytosol in response to oxidative stress and the pro-inflammatory cytokine interleukin-6. Tumor hypoxia may also be a contributor. Patients with EMAST colorectal cancers show diminished prognosis compared to patients without the presence of EMAST in their cancer. In addition to defective DNA MMR recognized by tetranucleotide (and di- and tri-nucleotide) frameshifts, loss of MSH3 also contributes to homologous recombination-mediated repair of DNA double stranded breaks, indicating the MSH3 dysfunction is a complex defect for cancer cells that generates not only EMAST but also may contribute to chromosomal instability and aneuploidy. Areas for future investigation for this most common DNA MMR defect among colorectal cancers include relationships between EMAST and chemotherapy response, patient outcome with aneuploid changes in colorectal cancers, target gene mutation analysis, and mechanisms related to inflammation-induced compartmentalization and inactivation for MSH3.
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15
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Kim JH, Kang GH. Molecular and prognostic heterogeneity of microsatellite-unstable colorectal cancer. World J Gastroenterol 2014; 20:4230-4243. [PMID: 24764661 PMCID: PMC3989959 DOI: 10.3748/wjg.v20.i15.4230] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2013] [Revised: 01/30/2014] [Accepted: 02/20/2014] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancers (CRCs) with a high level of microsatellite instability (MSI-H) are clinicopathologically distinct tumors characterized by predominance in females, proximal colonic localization, poor differentiation, mucinous histology, tumor-infiltrating lymphocytes, a Crohn’s-like lymphoid reaction and a favorable prognosis. In terms of their molecular features, MSI-H CRCs are heterogeneous tumors associated with various genetic and epigenetic alterations, including DNA mismatch repair deficiency, target microsatellite mutations, BRAF mutations, a CpG island methylator phenotype-high (CIMP-H) status, and a low level of genomic hypomethylation. The molecular heterogeneity of MSI-H CRCs also depends on ethnic differences; for example, in Eastern Asian countries, relatively low frequencies of CIMP-H and BRAF mutations have been observed in MSI-H CRCs compared to Western countries. Although the prognostic features of MSI-H CRCs include a favorable survival of patients and low benefit of adjuvant chemotherapy, there may be prognostic differences based on the molecular heterogeneity of MSI-H CRCs. Here, we have reviewed and discussed the molecular and prognostic features of MSI-H CRCs, as well as several putative prognostic or predictive molecular markers, including HSP110 expression, beta2-microglobulin mutations, myosin 1a expression, CDX2/CK20 expression, SMAD4 expression, CIMP status and LINE-1 methylation levels.
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16
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Should Microsatellite Instability Be Tested in All Cases of Colorectal Cancer? CURRENT COLORECTAL CANCER REPORTS 2014. [DOI: 10.1007/s11888-013-0204-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
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Abstract
UNLABELLED Colorectal cancer was one of the first solid tumors to be classified on the basis of molecular profiling. Microsatellite instability has allowed researchers to distinguish a specific subtype of colorectal cancer that has a clearly identified molecular origin (mismatch repair deficiency), arises on a hereditary and sporadic basis, is linked to a clear clinicopathologic profile, and has prognostic implications. Inconclusive predictive data along with a paucity of targeted drug development have prevented this molecular classification system from being implemented in the clinical setting. New high-throughput genomic data have validated it, thus stressing the fact that it is ready to be applied clinically. SIGNIFICANCE Application of a molecular classification of colorectal cancer in the clinical arena is an unmet promise. Recent results of large-scale genomic analyses have provided confirmation and further insights into the molecular biology of already known colorectal cancer subgroups. The quintessential example is the microsatellite instability subgroup, which has been well characterized during the past 2 decades. Future drug development and clinical research initiatives in colorectal oncology should consider these and other known cancer subgroups and start targeting these selected patient populations.
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Affiliation(s)
- Eduardo Vilar
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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18
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Furgason JM, Bahassi EM. Targeting DNA repair mechanisms in cancer. Pharmacol Ther 2012; 137:298-308. [PMID: 23107892 DOI: 10.1016/j.pharmthera.2012.10.009] [Citation(s) in RCA: 85] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2012] [Accepted: 10/11/2012] [Indexed: 12/21/2022]
Abstract
Preservation of genomic integrity is an essential process for cell homeostasis. DNA-damage response (DDR) promotes faithful transmission of genomes in dividing cells by reversing the extrinsic and intrinsic DNA damage, and is required for cell survival during replication. Radiation and genotoxic drugs have been widely used in the clinic for years to treat cancer but DNA repair mechanisms are often associated with chemo- and radio-resistance. To increase the efficacy of these treatments, inhibitors of the major components of the DDR such as ATM (ataxia telangiectasia mutated), ATR (ATM and Rad3-related), DNA-PK (DNA-dependent protein kinase, catalytic subunit), Chk1 (checkpoint protein 1) and Chk2 (checkpoint protein 2) have been used to confer radio- and/or chemosensitivity upon cancer cells. The elucidation of the molecular mechanisms of DNA repair and the discovery that tumors are frequently repair-deficient provide a therapeutic opportunity to selectively target this deficiency. Genetic mutations in the DNA repair genes constitute not only the initiating event of the cancer cell but also its weakness since the mutated gene is often needed by the cancer cell to maintain its own survival. This weakness has been exploited to specifically kill the tumor cells while sparing the normal ones, a concept known as 'synthetic lethality'. Recent efforts in the design of cancer therapies are directed towards exploiting synthetic lethal interactions with cancer-associated mutations in the DDR. In this review, we will discuss the latest concepts in targeting DNA repair mechanisms in cancer and the novel and promising compounds currently in clinical trials.
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Affiliation(s)
- John M Furgason
- Department of Internal Medicine, Division of Hematology/Oncology, University of Cincinnati, 3125 Eden Avenue, Cincinnati, OH 45267-0508, United States
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19
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Tomicic MT, Kaina B. Topoisomerase degradation, DSB repair, p53 and IAPs in cancer cell resistance to camptothecin-like topoisomerase I inhibitors. Biochim Biophys Acta Rev Cancer 2012; 1835:11-27. [PMID: 23006513 DOI: 10.1016/j.bbcan.2012.09.002] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2012] [Revised: 09/13/2012] [Accepted: 09/15/2012] [Indexed: 12/11/2022]
Abstract
Topoisomerase I (TOP1) inhibitors applied in cancer therapy such as topotecan and irinotecan are derivatives of the natural alkaloid camptothecin (CPT). The mechanism of CPT poisoning of TOP1 rests on inhibition of the re-ligation function of the enzyme resulting in the stabilization of the TOP1-cleavable complex. In the presence of CPTs this enzyme-DNA complex impairs transcription and DNA replication, resulting in fork stalling and the formation of DNA double-strand breaks (DSB) in proliferating cells. As with most chemotherapeutics, intrinsic and acquired drug resistance represents a hurdle that limits the success of CPT therapy. Preclinical data indicate that resistance to CPT-based drugs might be caused by factors such as (a) poor drug accumulation in the tumor, (b) high rate of drug efflux, (c) mutations in TOP1 leading to failure in CPT docking, or (d) altered signaling triggered by the drug-TOP1-DNA complex, (e) expression of DNA repair proteins, and (f) failure to activate cell death pathways. This review will focus on the issues (d-f). We discuss degradation of TOP1 as part of the repair pathway in the processing of TOP1 associated DNA damage, give a summary of proteins involved in repair of CPT-induced replication mediated DSB, and highlight the role of p53 and inhibitors of apoptosis proteins (IAPs), particularly XIAP and survivin, in cancer cell resistance to CPT-like chemotherapeutics.
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Affiliation(s)
- Maja T Tomicic
- Department of Toxicology, University Medical Center Mainz, Germany.
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20
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Ogino S, Shima K, Meyerhardt JA, McCleary NJ, Ng K, Hollis D, Saltz LB, Mayer RJ, Schaefer P, Whittom R, Hantel A, Benson AB, Spiegelman D, Goldberg RM, Bertagnolli MM, Fuchs CS. Predictive and prognostic roles of BRAF mutation in stage III colon cancer: results from intergroup trial CALGB 89803. Clin Cancer Res 2012; 18:890-900. [PMID: 22147942 PMCID: PMC3271172 DOI: 10.1158/1078-0432.ccr-11-2246] [Citation(s) in RCA: 228] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE Alterations in the RAS-RAF-MAP2K (MEK)-MAPK signaling pathway are major drivers in colorectal carcinogenesis. In colorectal cancer, BRAF mutation is associated with microsatellite instability (MSI), and typically predicts inferior prognosis. We examined the effect of BRAF mutation on survival and treatment efficacy in patients with stage III colon cancer. METHODS We assessed status of BRAF c.1799T>A (p.V600E) mutation and MSI in 506 stage III colon cancer patients enrolled in a randomized adjuvant chemotherapy trial [5-fluorouracil and leucovorin (FU/LV) vs. irinotecan (CPT11), FU and LV (IFL); CALGB 89803]. Cox proportional hazards model was used to assess the prognostic role of BRAF mutation, adjusting for clinical features, adjuvant chemotherapy arm, and MSI status. RESULTS Compared with 431 BRAF wild-type patients, 75 BRAF-mutated patients experienced significantly worse overall survival [OS; log-rank P = 0.015; multivariate HR = 1.66; 95% CI: 1.05-2.63]. By assessing combined status of BRAF and MSI, it seemed that BRAF-mutated MSS (microsatellite stable) tumor was an unfavorable subtype, whereas BRAF wild-type MSI-high tumor was a favorable subtype, and BRAF-mutated MSI-high tumor and BRAF wild-type MSS tumor were intermediate subtypes. Among patients with BRAF-mutated tumors, a nonsignificant trend toward improved OS was observed for IFL versus FU/LV arm (multivariate HR = 0.52; 95% CI: 0.25-1.10). Among patients with BRAF wild-type cancer, IFL conferred no suggestion of benefit beyond FU/LV alone (multivariate HR = 1.02; 95% CI: 0.72-1.46). CONCLUSIONS BRAF mutation is associated with inferior survival in stage III colon cancer. Additional studies are necessary to assess whether there is any predictive role of BRAF mutation for irinotecan-based therapy.
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Affiliation(s)
- Shuji Ogino
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02215, USA.
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21
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Rodriguez R, Rubio R, Gutierrez-Aranda I, Melen GJ, Elosua C, García-Castro J, Menendez P. FUS-CHOP fusion protein expression coupled to p53 deficiency induces liposarcoma in mouse but not in human adipose-derived mesenchymal stem/stromal cells. Stem Cells 2011; 29:179-92. [PMID: 21732477 DOI: 10.1002/stem.571] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
Human sarcomas have been modeled in mice by expression of specific fusion genes in mesenchymal stem cells (MSCs). However, sarcoma models based on human MSCs are still missing. We attempted to develop a model of liposarcoma by expressing FUS (FUsed in Sarcoma; also termed TLS, Translocated in LipoSarcoma)-CHOP (C/EBP HOmologous Protein; also termed DDIT3, DNA Damage-Inducible Transcript 3), a hallmark mixoid liposarcoma-associated fusion oncogene, in wild-type and p53-deficient mouse and human adipose-derived mesenchymal stem/stromal cells (ASCs). FUS-CHOP induced liposarcoma-like tumors when expressed in p53(-/-) but not in wild-type (wt) mouse ASCs (mASCs). In the absence of FUS-CHOP, p53(-/-) mASCs forms leiomyosarcoma, indicating that the expression of FUS-CHOP redirects the tumor genesis/phenotype. FUS-CHOP expression in wt mASCs does not initiate sarcomagenesis, indicating that p53 deficiency is required to induce FUS-CHOP-mediated liposarcoma in fat-derived mASCs. In a human setting, p53-deficient human ASCs (hASCs) displayed a higher in vitro growth rate and a more extended lifespan than wt hASCs. However, FUS-CHOP expression did not induce further changes in culture homeostasis nor initiated liposarcoma in either wt or p53-depleted hASCs. These results indicate that FUS-CHOP expression in a p53-deficient background is sufficient to initiate liposarcoma in mouse but not in hASCs, suggesting the need of additional cooperating mutations in hASCs. A microarray gene expression profiling has shed light into the potential deregulated pathways in liposarcoma formation from p53-deficient mASCs expressing FUS-CHOP, which might also function as potential cooperating mutations in the transformation process from hASCs.
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Affiliation(s)
- Rene Rodriguez
- Andalusian Stem Cell Bank, Centro de Investigación Biomédica, Consejería de Salud-Universidad de Granada, Granada, Spain.
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22
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Perspectives for tailored chemoprevention and treatment of colorectal cancer in Lynch syndrome. Crit Rev Oncol Hematol 2011; 80:264-77. [DOI: 10.1016/j.critrevonc.2010.11.009] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2010] [Revised: 11/03/2010] [Accepted: 11/18/2010] [Indexed: 12/22/2022] Open
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Wu X, Xu Y, Chai W, Her C. Causal link between microsatellite instability and hMRE11 dysfunction in human cancers. Mol Cancer Res 2011; 9:1443-8. [PMID: 21849470 DOI: 10.1158/1541-7786.mcr-11-0322] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Maintenance of genomic integrity is essential for cell survival, and genomic instability is a commonly recognized intrinsic property of all cancers. Microsatellite instability (MSI) represents a frequently occurring and easily traceable simple form of sequence variation, signified by the contraction or expansion of specific DNA sequences containing short tandem repeats. MSI is frequently detected in tumor cells with DNA mismatch repair (MMR) deficiency. It is commonly conceived that instability at individual microsatellite loci can arise spontaneously in cells independent of MMR status, and different microsatellite loci are generally not affected uniformly by MMR deficiency. It is well recognized that MMR deficiency per se is not sufficient to initiate tumorigenesis; rather, the biological effects have to be exerted by mutations in genes controlling cell survival, DNA damage response, and apoptosis. Recently, shortening of an intronic hMRE11 poly(T)11 tract has been associated with MMR deficiency, raising the possibility that hMRE11 may be inactivated by defective MMR. However, the molecular nature underlying this association is presently unknown, and review of the current literature suggests that hMRE11 is most likely involved with the MMR pathway in a more complex fashion than simply being a MMR target gene. An alternative scenario is proposed to better reconcile the differences among various studies. The potential role of hMRE11 in telomere repeats stability is also discussed.
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Affiliation(s)
- Xiling Wu
- School of Molecular Biosciences, Washington State University, Pullman, WA 99164, USA
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24
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Sinicrope FA, Yang ZJ. Prognostic and predictive impact of DNA mismatch repair in the management of colorectal cancer. Future Oncol 2011; 7:467-74. [PMID: 21417908 DOI: 10.2217/fon.11.5] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancers develop via two major pathways that include chromosomal instability and microsatellite instability. Microsatellite instability occurs due to deficient DNA mismatch repair (MMR), which can be caused by epigenetic silencing of the MLH1 MMR gene in sporadic colorectal cancers or germline mutations in MMR genes that result in Lynch syndrome. While the molecular origin of deficient MMR differs, sporadic and Lynch syndrome tumors share similar pathological features and have a more favorable stage-adjusted prognosis compared with MMR-proficient cases. While controversy remains, there is evidence to suggest that deficient MMR may predict a lack of benefit from 5-fluorouracil-based adjuvant chemotherapy. The focus of this article is on the MMR phenotype and its prognostic and predictive implications for the management of patients with colorectal cancer.
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Affiliation(s)
- Frank A Sinicrope
- Division of Oncology, Mayo Clinic & Mayo Cancer Center, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA.
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25
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Pino MS, Chung DC. Microsatellite instability in the management of colorectal cancer. Expert Rev Gastroenterol Hepatol 2011; 5:385-99. [PMID: 21651356 DOI: 10.1586/egh.11.25] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Microsatellite instability (MSI) is a form of genetic instability caused by alterations in the DNA mismatch repair system. Approximately 15% of colorectal cancers display MSI due to a germline mutation in one of the mismatch repair genes (MLH1, MSH2, MSH6 and PMS2) or to epigenetic silencing of MLH1. Colorectal cancers with MSI have distinctive features, including a tendency to arise in the proximal colon, poor differentiation, lymphocytic infiltration and mucinous or signet-ring histology. Patients with MSI tumors appear to have a better prognosis than those with microsatellite stable tumors, but curiously the responses to 5-fluorouracil-based chemotherapy regimens are poorer with MSI tumors. Preliminary data suggest possible advantages of irinotecan-based regimens, but these findings need validation in well-designed clinical trials.
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Affiliation(s)
- Maria S Pino
- Gastrointestinal Unit, Massachusetts General Hospital, 50 Blossom Street, Boston, MA 02114, USA
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Garner KM, Eastman A. Variations in Mre11/Rad50/Nbs1 status and DNA damage-induced S-phase arrest in the cell lines of the NCI60 panel. BMC Cancer 2011; 11:206:1-13. [PMID: 21619594 PMCID: PMC3128005 DOI: 10.1186/1471-2407-11-206] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2011] [Accepted: 05/27/2011] [Indexed: 12/03/2022] Open
Abstract
BACKGROUND The Mre11/Rad50/Nbs1 (MRN) complex is a regulator of cell cycle checkpoints and DNA repair. Defects in MRN can lead to defective S-phase arrest when cells are damaged. Such defects may elicit sensitivity to selected drugs providing a chemical synthetic lethal interaction that could be used to target therapy to tumors with these defects. The goal of this study was to identify these defects in the NCI60 panel of cell lines and identify compounds that might elicit selective cytotoxicity. METHODS We screened the NCI60 panel in search of cell lines that express low levels of MRN proteins, or that fail to arrest in S-phase in response to the topisomerase I inhibitor SN38. The NCI COMPARE program was used to discover compounds that preferentially target cells with these phenotypes. RESULTS HCT116 cells were initially identified as defective in MRN and S phase arrest. Transfection with Mre11 also elevated Rad50 and Nbs1, and rescued the defective S-phase arrest. Cells of the NCI60 panel exhibited a large range of protein expression but a strong correlation existed between Mre11, Rad50 and Nbs1 consistent with complex formation determining protein stability. Mre11 mRNA correlated best with protein level suggesting it was the primary determinant of the overall level of the complex. Three other cell lines failed to arrest in response to SN38, two of which also had low MRN. However, other cell lines with low MRN still arrested suggesting low MRN does not predict an inability to arrest. Many compounds, including a family of benzothiazoles, correlated with the failure to arrest in S phase. The activity of benzothiazoles has been attributed to metabolic activation and DNA alkylation, but we note several cell lines in which sensitivity does not correlate with metabolism. We propose that the checkpoint defect imposes an additional mechanism of sensitivity on cells. CONCLUSIONS We have identified cells with possible defects in the MRN complex and S phase arrest, and a series of compounds that may preferentially target S phase-defective cells. We discuss limitations of the COMPARE program when attempting to identify compounds that selectively inhibit only a few cell lines.
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Affiliation(s)
- Kristen M Garner
- Department of Pharmacology and Toxicology, and Norris Cotton Cancer Center, Dartmouth Medical School, Lebanon, NH 03756, USA
| | - Alan Eastman
- Department of Pharmacology and Toxicology, and Norris Cotton Cancer Center, Dartmouth Medical School, Lebanon, NH 03756, USA
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Zaanan A, Meunier K, Sangar F, Fléjou JF, Praz F. Microsatellite instability in colorectal cancer: from molecular oncogenic mechanisms to clinical implications. Cell Oncol (Dordr) 2011; 34:155-76. [PMID: 21484480 DOI: 10.1007/s13402-011-0024-x] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/13/2011] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Microsatellite instability (MSI) constitutes an important oncogenic molecular pathway in colorectal cancer (CRC), representing approximately 15% of all colorectal malignant tumours. In roughly one third of the cases, the underlying DNA mismatch repair (MMR) defect is inherited through the transmission of a mutation in one of the genes involved in MMR, predominantly MSH2 and MLH1, or less frequently, MSH6 or PMS2. In the overwhelming number of sporadic cases, MSI results from epigenetic MLH1 silencing through hypermethylation of its promoter. MMR deficiency promotes colorectal oncogenesis through the accumulation of numerous mutations in crucial target genes harbouring mononucleotide repeats, notably in those involved in the control of cell proliferation and differentiation, as well as DNA damage signalling and repair. DESIGN In this review, we describe the molecular aspects of the MMR system and the biological consequences of its defect on the oncogenic process, and we discuss the various experimental systems used to evaluate the efficacy of cytotoxic drugs on MSI colorectal cells lines. There is increasing evidence showing that MSI CRCs differ from all CRCs in terms of prognosis and response to the treatment. We report the clinical studies that have evaluated the prognostic and predictive value of MSI status on clinical outcome in patients treated with various chemotherapy regimens used in the adjuvant setting or for advanced CRCs. CONCLUSION In view of this, the opportunity of a systematic MSI phenotyping in the clinical management of patients with CRC is further discussed.
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Affiliation(s)
- Aziz Zaanan
- INSERM, UMR_S, Centre de Recherche Saint-Antoine, Paris, France
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28
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Takahashi M, Koi M, Balaguer F, Boland CR, Goel A. MSH3 mediates sensitization of colorectal cancer cells to cisplatin, oxaliplatin, and a poly(ADP-ribose) polymerase inhibitor. J Biol Chem 2011; 286:12157-65. [PMID: 21285347 DOI: 10.1074/jbc.m110.198804] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
The MSH3 gene is one of the DNA mismatch repair (MMR) genes that has undergone somatic mutation frequently in MMR-deficient cancers. MSH3, together with MSH2, forms the MutSβ heteroduplex, which interacts with interstrand cross-links (ICLs) induced by drugs such as cisplatin and psoralen. However, the precise role of MSH3 in mediating the cytotoxic effects of ICL-inducing agents remains poorly understood. In this study, we first examined the effects of MSH3 deficiency on cytotoxicity caused by cisplatin and oxaliplatin, another ICL-inducing platinum drug. Using isogenic HCT116-derived clones in which MSH3 expression is controlled by shRNA expression in a Tet-off system, we discovered that MSH3 deficiency sensitized cells to both cisplatin and oxaliplatin at clinically relevant doses. Interestingly, siRNA-induced down-regulation of the MLH1 protein did not affect MSH3-dependent toxicity of these drugs, indicating that this process does not require participation of the canonical MMR pathway. Furthermore, MSH3-deficient cells maintained higher levels of phosphorylated histone H2AX and 53BP1 after oxaliplatin treatment in comparison with MSH3-proficient cells, suggesting that MSH3 plays an important role in repairing DNA double strand breaks (DSBs). This role of MSH3 was further supported by our findings that MSH3-deficient cells were sensitive to olaparib, a poly(ADP-ribose) polymerase inhibitor. Moreover, the combination of oxaliplatin and olaparib exhibited a synergistic effect compared with either treatment individually. Collectively, our results provide novel evidence that MSH3 deficiency contributes to the cytotoxicity of platinum drugs through deficient DSB repair. These data lay the foundation for the development of effective prediction and treatments for cancers with MSH3 deficiency.
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Affiliation(s)
- Masanobu Takahashi
- Gastrointestinal Cancer Research Laboratory, Division of Gastroenterology, Department of Internal Medicine, Charles A. Sammons Cancer Center and Baylor Research Institute, Baylor University Medical Center, Dallas, Texas 75246-2017, USA
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29
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Na YS, Jung KA, Kim SM, Hong YS, Ryu MH, Jang SJ, Moon DH, Cho DH, Kim JC, Lee JS, Kim TW. The histone deacetylase inhibitor PXD101 increases the efficacy of irinotecan in in vitro and in vivo colon cancer models. Cancer Chemother Pharmacol 2010; 68:389-98. [PMID: 21046105 DOI: 10.1007/s00280-010-1495-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2010] [Accepted: 09/08/2010] [Indexed: 11/24/2022]
Abstract
PURPOSE Histone deacetylase inhibitors (HDACIs), such as PXD101 and suberoylanilide hydroxamic acid, inhibit proliferation and stimulate apoptosis of tumor cells. The enhanced effectiveness of chemotherapy or radiotherapy when combined with HDACIs has been observed in several cancers. In this study, we investigated the antitumor effect of PXD101 combined with irinotecan in colon cancer. METHODS HCT116 and HT29 colon cancer cells for cell viability assay were treated with PXD101 and/or SN-38, the active form of irinotecan. Antitumor effects of HCT116 and HT29 xenografts treated with these combinations were evaluated. [(18)F]FLT-PET was used to detect early responses to PXD101 and irinotecan in colon cancer. RESULTS PXD101 and SN38 possessed dose-dependent antiproliferative activity against HCT116 and HT29 cells and exerted a synergistic effect when used in combination. In xenografted mice, PXD101 in combination with irinotecan dramatically inhibited tumor growth without causing additive toxicity. Apoptotic effects on xenograft tumors were greater with combined treatment than with irinotecan alone. [(18)F]FLT-PET imaging revealed a 64% decrease in [(18)F]FLT uptake in tumors of HCT116 xenograft-bearing mice treated with a combination of PXD101 and irinotecan, indicating a decrease in thymidine kinase 1 (TK1) activity. These results were supported by Western blot analyses showing a decrease in tumor thymidine kinase 1 protein levels, suggesting that [(18)F]FLT-PET can be used to non-invasively detect early responses to these agents. CONCLUSIONS These data show that PXD101 increases the cytotoxic activity of irinotecan in in vitro and in vivo colon cancer models and suggest these agent combinations should be explored in the treatment of colon cancer.
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Affiliation(s)
- Young-Soon Na
- Institute for Innovate Cancer Research, Asan Medical Center, Seoul, Korea
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30
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Double strand break repair components are frequent targets of microsatellite instability in endometrial cancer. Eur J Cancer 2010; 46:2821-7. [DOI: 10.1016/j.ejca.2010.06.116] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2010] [Accepted: 06/18/2010] [Indexed: 11/22/2022]
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Martin SA, Lord CJ, Ashworth A. Therapeutic targeting of the DNA mismatch repair pathway. Clin Cancer Res 2010; 16:5107-13. [PMID: 20823149 DOI: 10.1158/1078-0432.ccr-10-0821] [Citation(s) in RCA: 109] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The mismatch repair (MMR) pathway is involved in the removal of DNA base mismatches that arise either during DNA replication or are caused by DNA damage. Mutations in four genes involved in MMR, MSH2, MLH1, PMS2 and MSH6, predispose to a range of tumorigenic conditions, including hereditary nonpolyposis colon cancer, also known as Lynch syndrome. Here we discuss the canonical MMR pathway and the burgeoning evidence for noncanonical roles for the MMR genes, and highlight the therapeutic implications of MMR. In particular, we discuss how the DNA repair defect in MMR-deficient cancers could be exploited by the development of novel therapeutic strategies based on synthetic lethal approaches.
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Affiliation(s)
- Sarah A Martin
- Cancer Research UK Gene Function and Regulation Group, The Institute of Cancer Research, London, United Kingdom
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Abstract
Microsatellite instability (MSI) is the molecular fingerprint of a deficient mismatch repair system. Approximately 15% of colorectal cancers (CRC) display MSI owing either to epigenetic silencing of MLH1 or a germline mutation in one of the mismatch repair genes MLH1, MSH2, MSH6 or PMS2. Methods to detect MSI are well established and routinely incorporated into clinical practice. A clinical and molecular profile of MSI tumors has been described, leading to the concept of an MSI phenotype in CRC. Studies have confirmed that MSI tumors have a better prognosis than microsatellite stable CRC, but MSI cancers do not necessarily have the same response to the chemotherapeutic strategies used to treat microsatellite stable tumors. Specifically, stage II MSI tumors might not benefit from 5-fluorouracil-based adjuvant chemotherapy regimens. New data suggest possible advantages of irinotecan-based regimens, but these findings require further clarification. Characterization of the molecular basis of MSI in CRC is underway and initial results show that mutations in genes encoding kinases and candidate genes with microsatellite tracts are over-represented in MSI tumors. Transcriptome expression profiles of MSI tumors and systems biology approaches are providing the opportunity to develop targeted therapeutics for MSI CRC.
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Affiliation(s)
- Eduardo Vilar
- Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA
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Hewish M, Lord CJ, Martin SA, Cunningham D, Ashworth A. Mismatch repair deficient colorectal cancer in the era of personalized treatment. Nat Rev Clin Oncol 2010; 7:197-208. [DOI: 10.1038/nrclinonc.2010.18] [Citation(s) in RCA: 165] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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Martin SA, Hewish M, Lord CJ, Ashworth A. Genomic instability and the selection of treatments for cancer. J Pathol 2010; 220:281-9. [PMID: 19890832 DOI: 10.1002/path.2631] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
A critical link exists between DNA mutation and chromosomal rearrangements (genomic instability) and cancer development. This genomic instability can manifest itself as small changes at the nucleotide level or as gross chromosomal alterations. Mutations in the genes that encode DNA damage response proteins are responsible for a variety of genomic instability syndromes including hereditary non-polyposis colorectal carcinoma, Bloom's syndrome, ataxia-telangiectasia, BRCA-associated breast and ovarian cancers and Fanconi anaemia. Similarly, epigenetic silencing of genes associated with the maintenance of genomic stability have also been implicated in the pathogenesis of cancer. Here, we discuss how different tumours may be classified not only by tumour site but also by the type of underlying genetic instability. This type of classification may assist in the optimization of existing treatment regimens as well as informing the development of new therapeutic approaches.
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Affiliation(s)
- Sarah A Martin
- CRUK Gene Function Laboratory, Institute of Cancer Research, Fulham Road, London SW3 6JB, UK
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Nash GM, Gimbel M, Cohen AM, Zeng ZS, Ndubuisi MI, Nathanson DR, Ott J, Barany F, Paty PB. KRAS mutation and microsatellite instability: two genetic markers of early tumor development that influence the prognosis of colorectal cancer. Ann Surg Oncol 2009; 17:416-24. [PMID: 19813061 DOI: 10.1245/s10434-009-0713-0] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2009] [Indexed: 12/12/2022]
Abstract
INTRODUCTION We examined two genetic markers established early in colorectal tumor development, microsatellite instability (MSI) and mutation of the KRAS proto-oncogene, to see if these genetic changes influence metastatic disease progression and survival. PATIENTS AND METHODS MSI and KRAS mutation status were assessed in 532 primary adenocarcinomas (stage I-IV) from patients treated by colon resection. Median follow-up was 4.1 years (range 0-13.3 years) overall, 5.4 years for survivors. RESULTS MSI and KRAS mutation were detected in 12 and 36% of cases, respectively. MSI was more common in early-stage disease (I, 15%; II, 21%; III, 10%; IV, 2%; P = 0.0001). Prevalence of KRAS mutation did not vary with stage (I, 36%; II, 34%; III, 35%; IV, 40%; P = ns). Disease-specific survival was far superior for MSI tumors than for microsatellite stability (MSS) tumors (5-year survival 92 vs. 59%, P < 0.0001). KRAS mutation was a marker of poor survival (5-year survival 55 vs. 68%, P = 0.0002). Using Cox regression analysis MSI, KRAS mutation, and stage were strong independent predictors of survival in the entire patient population. A high-mortality group with MSS/KRAS-mutant tumors was identified within the stage I and II cohort. CONCLUSIONS MSI and KRAS mutation provide fundamental genetic signatures influencing tumor behavior across patient subsets and stages of tumor development.
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Affiliation(s)
- Garrett M Nash
- Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, USA
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