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The cell of cancer origin provides the most reliable roadmap to its diagnosis, prognosis (biology) and therapy. Med Hypotheses 2021; 157:110704. [PMID: 34688214 DOI: 10.1016/j.mehy.2021.110704] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Accepted: 10/06/2021] [Indexed: 11/21/2022]
Abstract
Cancers arise from single transformed cells from virtually every organ of the body, divide in a relatively uncontrolled manner, and metastasize widely. A search for a "magic bullet" to precisely diagnose, characterize, and ultimately treat cancer has largely failed because cancer cells do not differ significantly from their organ-specific cells of origin. Instead of searching for genomic, epigenetic, transcriptional, and translational differences between cancers and their cells of origin, we should paradoxically focus on what cancer cells have in common with their untransformed cells of origin. This redirected search will lead to improved diagnostic and therapeutic strategies where therapeutic index considerations and drug-limiting toxicities can largely be circumvented. We cite three cancer examples that illustrate this paradigm-shifting strategy: pseudomyxoma peritonei (PP), metastasis of unknown origin (cancers of unknown primary) (MUO), and cancers that arise from potentially dispensable organs (CAD). In each of these examples, the cell of cancer origin still provides the most reliable road map to its diagnosis, prognosis (biology), and therapy.
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Nguyen C, Nguyen JPT, Modi AP, Ahmad I, Petrova SC, Ferrell SD, Wilhelm SR, Ye Y, Schaue D, Barsky SH. Use of constitutive and inducible oncogene-containing iPSCs as surrogates for transgenic mice to study breast oncogenesis. Stem Cell Res Ther 2021; 12:301. [PMID: 34044885 PMCID: PMC8162012 DOI: 10.1186/s13287-021-02285-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Accepted: 03/12/2021] [Indexed: 11/25/2022] Open
Abstract
BACKGROUND Powerful constitutive and inducible transgenic / bitransgenic / tritransgenic murine models of breast cancer have been used over the past two decades to shed light on the molecular mechanisms by which the given transgenic oncogenes have interacted with other cellular genes and set in motion breast cancer initiation and progression. However, these transgenic models, as in vivo models only, are expensive and restrictive in the opportunities they provide to manipulate the experimental variables that would enable a better understanding of the molecular events related to initial transformation and the target cell being transformed. METHODS To overcome some of these limitations, we derived oncogene-containing induced pluripotent stem cell (iPSC) clones from tail vein fibroblasts of these transgenic mice and manipulated them both in vitro and in vivo in non-transgenic background mice. We created the iPSC clones with a relatively low M.O.I, producing retroviral integrations which averaged only 1 to 2 sites per retroviral plasmid construct used. RESULTS Most iPSC clones derived from each group displayed an essentially normal murine karyotype, strong expression of the exogenous reprogrammable genes and significant expression of characteristic endogenous murine surface stem cell markers including SSEA-1 (CD15), PECAM-1 (CD31), Ep-Cam (CD326), and Nectin (CD112), but no expression of their transgene. A majority (75%) of iPSC clones displayed a normal murine karyotype but 25% exhibited a genomically unstable karyotype. However, even these later clones exhibited stable and characteristic iPSC properties. When injected orthotopically, select iPSC clones, either constitutive or inducible, no longer expressed their exogenous pluripotency reprogramming factors but expressed their oncogenic transgene (PyVT or ErbB2) and participated in both breast ontogenesis and subsequent oncogenesis. When injected non-orthotopically or when differentiated in vitro along several different non-mammary lineages of differentiation, the iPSC clones failed to do so. Although many clones developed anticipated teratomas, select iPSC clones under the appropriate constitutive or inducible conditions exhibited both breast ontogenesis and oncogenesis through the same stages as exhibited by their transgenic murine parents and, as such, represent transgenic surrogates. CONCLUSIONS The iPSC clones offer a number of advantages over transgenic mice including cost, the ability to manipulate and tag in vitro, and create an in vitro model of breast ontogeny and oncogenesis that can be used to gain additional insights into the differentiated status of the target cell which is susceptible to transformation. In addition, the use of these oncogene-containing iPSC clones can be used in chemopreventive studies of breast cancer.
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Affiliation(s)
- Christine Nguyen
- Cancer Center and Institute for Personalized Medicine, California University of Science and Medicine (CUSM), 1501 Violet Street, Colton, CA, 92324, USA
| | - Julie P T Nguyen
- Cancer Center and Institute for Personalized Medicine, California University of Science and Medicine (CUSM), 1501 Violet Street, Colton, CA, 92324, USA
| | - Arnav P Modi
- Cancer Center and Institute for Personalized Medicine, California University of Science and Medicine (CUSM), 1501 Violet Street, Colton, CA, 92324, USA
| | - Ihsaan Ahmad
- Cancer Center and Institute for Personalized Medicine, California University of Science and Medicine (CUSM), 1501 Violet Street, Colton, CA, 92324, USA
| | - Sarah C Petrova
- Cancer Center and Institute for Personalized Medicine, California University of Science and Medicine (CUSM), 1501 Violet Street, Colton, CA, 92324, USA
| | - Stuart D Ferrell
- Cancer Center and Institute for Personalized Medicine, California University of Science and Medicine (CUSM), 1501 Violet Street, Colton, CA, 92324, USA
| | - Sabrina R Wilhelm
- Cancer Center and Institute for Personalized Medicine, California University of Science and Medicine (CUSM), 1501 Violet Street, Colton, CA, 92324, USA
| | - Yin Ye
- Cancer Center and Institute for Personalized Medicine, California University of Science and Medicine (CUSM), 1501 Violet Street, Colton, CA, 92324, USA
| | - Dorthe Schaue
- Department of Radiation Oncology, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095-1714, USA
| | - Sanford H Barsky
- Cancer Center and Institute for Personalized Medicine, California University of Science and Medicine (CUSM), 1501 Violet Street, Colton, CA, 92324, USA.
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3
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Petrova SC, Ahmad I, Nguyen C, Ferrell SD, Wilhelm SR, Ye Y, Barsky SH. Regulation of breast cancer oncogenesis by the cell of origin's differentiation state. Oncotarget 2020; 11:3832-3848. [PMID: 33196707 PMCID: PMC7597414 DOI: 10.18632/oncotarget.27783] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Accepted: 09/24/2020] [Indexed: 12/25/2022] Open
Abstract
Human breast cancer which affects 1/8 women is rare at a cellular level. Even in the setting of germline BRCA1/BRCA2, which is present in all breast cells, solitary cancers or cancers arising at only several foci occur. The overwhelming majority of breast cells (109-1012 cells) resist transformation. Our hypothesis to explain this rareness of transformation is that mammary oncogenesis is regulated by the cell of origin's critical window of differentiation so that target cells outside of this window cannot transform. Our novel hypothesis differs from both the multi-hit theory of carcinogenesis and the stem/progenitor cell compartmental theory of tumorigenesis and utilizes two well established murine transgenic models of breast oncogenesis, the FVB/N-Tg (MMTV-PyVT)634Mul/J and the FVB-Tg (MMTV-ErbB2) NK1Mul/J. Tail vein fibroblasts from each of these transgenics were used to generate iPSCs. When select clones were injected into cleared mammary fat pads, but not into non-orthotopic sites of background mice, they exhibited mammary ontogenesis and oncogenesis with the expression of their respective transgenes. iPSC clones, when differentiated along different non-mammary lineages in vitro, were also not able to exhibit either mammary ontogenesis or oncogenesis in vivo. Therefore, in vitro and in vivo regulation of differentiation is an important determinant of breast cancer oncogenesis.
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Affiliation(s)
- Sarah C Petrova
- Cancer Center and Institute for Personalized Medicine, California University of Science and Medicine, Colton, CA 92324, USA.,These authors contributed equally to this work
| | - Ihsaan Ahmad
- Cancer Center and Institute for Personalized Medicine, California University of Science and Medicine, Colton, CA 92324, USA.,These authors contributed equally to this work
| | - Christine Nguyen
- Cancer Center and Institute for Personalized Medicine, California University of Science and Medicine, Colton, CA 92324, USA
| | - Stuart D Ferrell
- Cancer Center and Institute for Personalized Medicine, California University of Science and Medicine, Colton, CA 92324, USA
| | - Sabrina R Wilhelm
- Cancer Center and Institute for Personalized Medicine, California University of Science and Medicine, Colton, CA 92324, USA
| | - Yin Ye
- Cancer Center and Institute for Personalized Medicine, California University of Science and Medicine, Colton, CA 92324, USA
| | - Sanford H Barsky
- Cancer Center and Institute for Personalized Medicine, California University of Science and Medicine, Colton, CA 92324, USA
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4
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Ferrell SD, Ahmad I, Nguyen C, Petrova SC, Wilhelm SR, Ye Y, Barsky SH. Why is cancer so common a disease in people yet so rare at a cellular level? Med Hypotheses 2020; 144:110171. [PMID: 33254495 DOI: 10.1016/j.mehy.2020.110171] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Accepted: 08/06/2020] [Indexed: 11/17/2022]
Abstract
Cancers are common diseases in people and yet, on a cellular level, are quite rare. The vast majority of both sporadic, spontaneous cancers and inherited germline cancers arise in single foci from singly transformed cells despite the fact that, in the former, carcinogenic factors bathe fields of millions of potential target cells and, in the latter, the predisposing germline mutations are present in every cell of a given organ and, in fact, every cell of the body. Although the multi-hit theory of carcinogenesis has been invoked to explain such things as cancer latency, which is the period between cancer initiation and emergence and the cancer-aging relationship where an accumulation of "hits" over a period of time are necessary for cancer emergence, the multi-hit theory falls short in explaining the rareness of transformation at a cellular level. This is so because many cancers are not due to multiple hits, and even for those that are, it would be expected that many cells would be exposed to those factors inducing the hits. Although the tumor stem/progenitor cell compartmental theory of tumorigenesis characterizes a tumor compartment that is capable of self-renewal and multipotency, accounting for cancer relapses and recurrences, this compartmental theory alone cannot account for the rareness of initial transformation at a cellular level as the cancer stem/progenitor cell compartment is already transformed and considerable in size. This study advances a different and novel hypothesis that oncogenesis is regulated and ultimately determined by a cell of origin's critical state of differentiation. Before and after this critical state of differentiation has been reached, target cells cannot transform and give rise to cancer even when they receive the necessary carcinogenic insults or have the requisite transforming tumor suppressor genes or oncogenes. As support for this hypothesis, the study cites preliminary evidence using oncogene-containing transgenic mice that develop mammary carcinomas, to derive tail vein fibroblasts converted to iPSCs which, when left undifferentiated, and injected into the cleared fat pads of non-transgenic background mice give rise to mammary gland ontogeny and mammary gland carcinogenesis. However, when first differentiated in vitro into multiply different non-mammary lineages prior to injection, they fail to do so. The hypothesis has widespread implications for chemopreventive strategies.
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Affiliation(s)
- Stuart D Ferrell
- Cancer Center and Institute for Personalized Medicine, California University of Science and Medicine, 1501 Violet Street, Colton, CA 92324, USA
| | - Ihsaan Ahmad
- Cancer Center and Institute for Personalized Medicine, California University of Science and Medicine, 1501 Violet Street, Colton, CA 92324, USA
| | - Christine Nguyen
- Cancer Center and Institute for Personalized Medicine, California University of Science and Medicine, 1501 Violet Street, Colton, CA 92324, USA
| | - Sarah C Petrova
- Cancer Center and Institute for Personalized Medicine, California University of Science and Medicine, 1501 Violet Street, Colton, CA 92324, USA
| | - Sabrina R Wilhelm
- Cancer Center and Institute for Personalized Medicine, California University of Science and Medicine, 1501 Violet Street, Colton, CA 92324, USA
| | - Yin Ye
- Cancer Center and Institute for Personalized Medicine, California University of Science and Medicine, 1501 Violet Street, Colton, CA 92324, USA
| | - Sanford H Barsky
- Cancer Center and Institute for Personalized Medicine, California University of Science and Medicine, 1501 Violet Street, Colton, CA 92324, USA.
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Assoun EN, Meyer AN, Jiang MY, Baird SM, Haas M, Donoghue DJ. Characterization of iPS87, a prostate cancer stem cell-like cell line. Oncotarget 2020; 11:1075-1084. [PMID: 32256979 PMCID: PMC7105161 DOI: 10.18632/oncotarget.27524] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Accepted: 03/03/2020] [Indexed: 12/31/2022] Open
Abstract
Prostate cancer affects hundreds of thousands of men and families throughout the world. Although chemotherapy, radiation, surgery, and androgen deprivation therapy are applied, these therapies do not cure metastatic prostate cancer. Patients treated by androgen deprivation often develop castration resistant prostate cancer which is incurable. Novel approaches of treatment are clearly necessary. We have previously shown that prostate cancer originates as a stem cell disease. A prostate cancer patient sample, #87, obtained from prostatectomy surgery, was collected and frozen as single cell suspension. Cancer stem cell cultures were grown, single cell-cloned, and shown to be tumorigenic in SCID mice. However, outside its natural niche, the cultured prostate cancer stem cells lost their tumor-inducing capability and stem cell marker expression after approximately 8 transfers at a 1:3 split ratio. Tumor-inducing activity could be restored by inducing the cells to pluripotency using the method of Yamanaka. Cultures of human prostate-derived normal epithelial cells acquired from commercial sources were similarly induced to pluripotency and these did not acquire a tumor phenotype in vivo. To characterize the iPS87 cell line, cells were stained with antibodies to various markers of stem cells including: ALDH7A1, LGR5, Oct4, Nanog, Sox2, Androgen Receptor, and Retinoid X Receptor. These markers were found to be expressed by iPS87 cells, and the high tumorigenicity in SCID mice of iPS87 was confirmed by histopathology. This research thus characterizes the iPS87 cell line as a cancer-inducing, stem cell-like cell line, which can be used in the development of novel treatments for prostate cancer.
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Affiliation(s)
- Erika N. Assoun
- Division of Biological Sciences, University of California San Diego, La Jolla, San Diego, CA 92093, USA
| | - April N. Meyer
- Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, San Diego, CA 92093, USA
| | - Maggie Y. Jiang
- Division of Biological Sciences, University of California San Diego, La Jolla, San Diego, CA 92093, USA
| | - Stephen M. Baird
- Department of Pathology, University of California San Diego, La Jolla, San Diego, CA 92093, USA
| | - Martin Haas
- Moores UCSD Cancer Center, University of California San Diego, La Jolla, San Diego, CA 92093, USA
| | - Daniel J. Donoghue
- Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, San Diego, CA 92093, USA
- Moores UCSD Cancer Center, University of California San Diego, La Jolla, San Diego, CA 92093, USA
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6
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Cancer stem cell fate determination: a nuclear phenomenon. THE NUCLEUS 2019. [DOI: 10.1007/s13237-019-00281-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
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7
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Rationales for the Use of Cancer Stem Cells Markers in the Staging of Papillary Thyroid Carcinoma. JOURNAL OF ONCOLOGY 2019; 2019:1659654. [PMID: 31341476 PMCID: PMC6613036 DOI: 10.1155/2019/1659654] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/02/2019] [Accepted: 05/23/2019] [Indexed: 01/04/2023]
Abstract
Fine needle aspiration biopsy (FNAB) is a standard procedure for the detection of thyroid nodules malignancy, yet 10-25% of the sample diagnosed may go undetermined or suspicious. The utility of cancer stem cell markers (CSCM) as a differential diagnosis molecular marker in nodules of suspicious decision in FNAB was hypothesized. Papillary thyroid carcinoma (PTC) and thyroid fibroadenoma (TFA) samples were selected to test the hypothesis. The samples employed in this study were from patients who had thyroid hyperplasia and a suspicious or undetermined diagnosis by FNAB. The patient underwent a successful thyroidectomy at Al-Yarmouk Teaching Hospital in Baghdad between January 2015 and December 2017. All nodule samples underwent a systematic histopathological examination after resection. Tumors diagnosed as PTC and those diagnosed as fibroadenoma (TFA) were selected for this study. Collectively 39 PTC and 11 TFA nodules were included. Quantitative reverse transcriptase real-time PCR (qRT-PCR) and immunohistochemistry (IHC) were used to determine levels of mRNA and proteins of CSCM ALDH1A1, CD44, ABCG2, and Oct3/4 in both types of tumors were used. This study revealed that the expression levels of CSCM were significantly increased in PTC tissues when compared to benign tissues and the positive correlation was found between the CSCM expression levels and tumor stage, size, and gender. In conclusion, for a more precise diagnosis, we suggest these markers be included in what is currently available to characterize malignancy from what is not in thyroid cancer, as well as for the staging process of PTC.
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8
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Marzagalli M, Raimondi M, Fontana F, Montagnani Marelli M, Moretti RM, Limonta P. Cellular and molecular biology of cancer stem cells in melanoma: Possible therapeutic implications. Semin Cancer Biol 2019; 59:221-235. [PMID: 31265892 DOI: 10.1016/j.semcancer.2019.06.019] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2019] [Accepted: 06/27/2019] [Indexed: 01/17/2023]
Abstract
Malignant melanoma is a tumor characterized by a very high level of heterogeneity, responsible for its malignant behavior and ability to escape from standard therapies. In this review we highlight the molecular and biological features of the subpopulation of cancer stem cells (CSCs), well known to be characterized by self-renewal properties, deeply involved in triggering the processes of tumor generation, metastasis, progression and drug resistance. From the molecular point of view, melanoma CSCs are identified and characterized by the expression of stemness markers, such as surface markers, ATP-binding cassette (ABC) transporters, embryonic stem cells and intracellular markers. These cells are endowed with different functional features. In particular, they play pivotal roles in the processes of tumor dissemination, epithelial-to-mesenchymal transition (EMT) and angiogenesis, mediated by specific intracellular signaling pathways; moreover, they are characterized by a unique metabolic reprogramming. As reported for other types of tumors, the CSCs subpopulation in melanoma is also characterized by a low immunogenic profile as well as by the ability to escape the immune system, through the expression of a negative modulation of T cell functions and the secretion of immunosuppressive factors. These biological features allow melanoma CSCs to escape standard treatments, thus being deeply involved in tumor relapse. Targeting the CSCs subpopulation is now considered an attractive treatment strategy; in particular, combination treatments, based on both CSCs-targeting and standard drugs, will likely increase the therapeutic options for melanoma patients. The characterization of CSCs in liquid biopsies from single patients will pave the way towards precision medicine.
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Affiliation(s)
- Monica Marzagalli
- Department of Pharmacological and Biomolecular Sciences, University of Milano, Milano, Italy
| | - Michela Raimondi
- Department of Pharmacological and Biomolecular Sciences, University of Milano, Milano, Italy
| | - Fabrizio Fontana
- Department of Pharmacological and Biomolecular Sciences, University of Milano, Milano, Italy
| | | | - Roberta M Moretti
- Department of Pharmacological and Biomolecular Sciences, University of Milano, Milano, Italy
| | - Patrizia Limonta
- Department of Pharmacological and Biomolecular Sciences, University of Milano, Milano, Italy.
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9
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Aghaalikhani N, Rashtchizadeh N, Shadpour P, Allameh A, Mahmoodi M. Cancer stem cells as a therapeutic target in bladder cancer. J Cell Physiol 2018; 234:3197-3206. [PMID: 30471107 DOI: 10.1002/jcp.26916] [Citation(s) in RCA: 63] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2018] [Accepted: 06/13/2018] [Indexed: 12/13/2022]
Abstract
Bladder cancer is one of the most prevalent genitourinary cancers responsible for about 150,000 deaths per year worldwide. Currently, several treatments, such as endoscopic and open surgery, appended by local or systemic immunotherapy, chemotherapy, and radiotherapy are used to treat this malignancy. However, the differences in treatment outcome among patients suffering from bladder cancer are considered as one of the important challenges. In recent years, cancer stem cells, representing a population of undifferentiated cells with stem-cell like properties, have been eyed as a major culprit for the high recurrence rate in superficial papillary bladder cancer. Cancer stem cells have been reported to be resistant to conventional treatments, such as chemotherapy, radiation, and immunotherapy, which induce selective pressure on tumoral populations resulting in selection and growth of the resistant cells. Therefore, targeting the therapeutic aspects of cancer stem cells in bladder cancer may be promising. In this study, we briefly discuss the biology of bladder cancer and then address the possible relationship between molecular biology of bladder cancer and cancer stem cells. Subsequently, the mechanisms of resistance applied by cancer stem cells against the conventional therapeutic tools, especially chemotherapy, are discussed. Moreover, by emphasizing the biomarkers described for cancer stem cells in bladder cancer, we have provided, described, and proposed targets on cancer stem cells for therapeutic interventions and, finally, reviewed some immunotargeting strategies against bladder cancer stem cells.
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Affiliation(s)
- Nazi Aghaalikhani
- Department of Clinical Biochemistry and Laboratory Sciences, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.,Drug Applied Research Centre, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Nadereh Rashtchizadeh
- Department of Clinical Biochemistry and Laboratory Sciences, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.,Drug Applied Research Centre, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Pejman Shadpour
- Hasheminejad Kidney Centre (HKC), Hospital Management Research Centre (HMRC), University of Medical Sciences (IUMS), Tehran, Iran
| | - Abdolamir Allameh
- Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Marzieh Mahmoodi
- Faculty of Health and Nutrition, Bushehr University of Medical Sciences, Bushehr, Iran
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10
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Jiang MY, Lee TL, Hao SS, Mahooti S, Baird SM, Donoghue DJ, Haas M. Visualization of early prostatic adenocarcinoma as a stem cell disease. Oncotarget 2018; 7:76159-76168. [PMID: 27764770 PMCID: PMC5342804 DOI: 10.18632/oncotarget.12709] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2016] [Accepted: 10/07/2016] [Indexed: 12/25/2022] Open
Abstract
Prostate Cancer represents the second leading cause of cancer death among men in the United States, and the third leading cause of cancer death among men in Europe. We have previously shown that cells possessing Cancer Stem Cell (CSC) characteristics can be grown from human PrCa tissue harvested at the time of prostatectomy. However, the cellular origin of these CSCs was not previously known. In most cases, simple hematoxylin and eosin (H&E) stained sections are sufficient to make a definitive diagnosis of prostatic adenocarcinoma (PrCa) in needle biopsy samples. We utilized six different antibodies specific for stem cell antigens to examine paraffin sections of PrCa taken at the time of needle-biopsy diagnosis. These antisera were specific for CD44, CD133, ALDH7A1, LGR-5, Oct-4 and NANOG. We demonstrate specific staining of tumor cells with all six antisera specific for stem cell antigens. Some of these antibodies also react with cells of hyperplastic glands, but the patterns of reactivity differ from those of malignant glands. These findings demonstrate that at the time of diagnosis, PrCa consists of cells exhibiting properties of CSCs and consistent with the possibility that PrCa is a stem cell disease.
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Affiliation(s)
- Maggie Y Jiang
- Moores UCSD Cancer Center, University of California San Diego, La Jolla, CA 92093, USA.,Division of Biological Sciences, University of California San Diego, La Jolla, CA 92093, USA
| | - Tammy L Lee
- Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA 92093, USA
| | - Su-Shin Hao
- Division of Biological Sciences, University of California San Diego, La Jolla, CA 92093, USA
| | - Sepi Mahooti
- Department of Pathology, University of California San Diego, La Jolla, CA 92093, USA
| | - Stephen M Baird
- Department of Pathology, University of California San Diego, La Jolla, CA 92093, USA
| | - Daniel J Donoghue
- Moores UCSD Cancer Center, University of California San Diego, La Jolla, CA 92093, USA.,Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA 92093, USA
| | - Martin Haas
- Moores UCSD Cancer Center, University of California San Diego, La Jolla, CA 92093, USA.,Division of Biological Sciences, University of California San Diego, La Jolla, CA 92093, USA
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11
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Cancer stem cell markers in prostate cancer: an immunohistochemical study of ALDH1, SOX2 and EZH2. Pathology 2016; 47:622-8. [PMID: 26517640 DOI: 10.1097/pat.0000000000000325] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
The aims of this study were to investigate the immunohistochemical expression and potential prognostic significance of putative cancer stems cell markers ALDH1, EZH2 and SOX2 in prostate cancer.A total of 142 consecutive radical prostatectomies submitted to one laboratory with a diagnosis of prostatic adenocarcinoma between 2008 and 2012 were retrieved and retrospectively studied. Immunohistochemistry for the three markers was performed in each case and both univariate and multivariate analyses were undertaken to evaluate the correlation between the staining patterns and known histopathological prognostic features.ALDH1 showed a statistically significant association with tumour stage p < 0.001), extraprostatic extension (p < 0.001) and lymphovascular invasion (p = 0.001). EZH2 correlated with Gleason score (p = 0.044) and lymph node metastases (p = 0.023). SOX2 showed a statistically significant correlation with lymphovascular invasion only (p = 0.018) in both univariate and multivariate analyses.Cancer stem cell markers are variably expressed in prostate adenocarcinoma and immunohistochemical staining for ALDH1 and EZH2 may have a role in predicting tumour aggressiveness before treatment of prostate cancer.
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12
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Friberg S, Nyström AM. NANOMEDICINE: will it offer possibilities to overcome multiple drug resistance in cancer? J Nanobiotechnology 2016; 14:17. [PMID: 26955956 PMCID: PMC4784447 DOI: 10.1186/s12951-016-0172-2] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2015] [Accepted: 03/03/2016] [Indexed: 12/12/2022] Open
Abstract
This review is written with the purpose to review the current nanomedicine literature and provide an outlook on the developments in utilizing nanoscale drug constructs in treatment of solid cancers as well as in the potential treatment of multi-drug resistant cancers. No specific design principles for this review have been utilized apart from our active choice to avoid results only based on in vitro studies. Few drugs based on nanotechnology have progressed to clinical trials, since most are based only on in vitro experiments which do not give the necessary data for the research to progress towards pre-clinical studies. The area of nanomedicine has indeed spark much attention and holds promise for improved future therapeutics in the treatment of solid cancers. However, despite much investment few targeted therapeutics have successfully progressed to early clinical trials, indicating yet again that the human body is complicated and that much more understanding of the fundamentals of receptor interactions, physics of nanomedical constructs and their circulation in the body is indeed needed. We believe that nanomedical therapeutics can allow for more efficient treatments of resistant cancers, and may well be a cornerstone for RNA based therapeutics in the future given their general need for shielding from the harsh environment in the blood stream.
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Affiliation(s)
- Sten Friberg
- Department of Neuroscience, Swedish Medical Nanoscience Center, Karolinska Institutet, Retzius väg 8, 171 77, Stockholm, Sweden.
| | - Andreas M Nyström
- Institute of Environmental Medicine, Karolinska Institutet, Nobels väg 13, 171 77, Stockholm, Sweden.
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13
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Zamarrón A, Lucena SR, Salazar N, Sanz-Rodríguez F, Jaén P, Gilaberte Y, González S, Juarranz Á. Isolation and characterization of PDT-resistant cancer cells. Photochem Photobiol Sci 2015; 14:1378-89. [DOI: 10.1039/c4pp00448e] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Even though the efficacy of photodynamic therapy (PDT) for treating premalignant and malignant lesions has been demonstrated, resistant tumor cells to this therapy occasionally appear.
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Affiliation(s)
- Alicia Zamarrón
- Department of Biology
- Facultad de Ciencias
- Universidad Autónoma de Madrid
- Cantoblanco 28049
- Spain
| | - Silvia R. Lucena
- Department of Biology
- Facultad de Ciencias
- Universidad Autónoma de Madrid
- Cantoblanco 28049
- Spain
| | - Nerea Salazar
- Department of Biology
- Facultad de Ciencias
- Universidad Autónoma de Madrid
- Cantoblanco 28049
- Spain
| | | | - Pedro Jaén
- Department of Dermatology
- Hospital Ramón y Cajal
- Madrid
- Spain
- Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS)
| | - Yolanda Gilaberte
- Department of Dermatology
- Hospital San Jorge
- Huesca
- Spain
- Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS)
| | - Salvador González
- Department of Dermatology
- Hospital Ramón y Cajal
- Madrid
- Spain
- Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS)
| | - Ángeles Juarranz
- Department of Biology
- Facultad de Ciencias
- Universidad Autónoma de Madrid
- Cantoblanco 28049
- Spain
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14
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Akhavan-Niaki H, Samadani AA. Molecular insight in gastric cancer induction: an overview of cancer stemness genes. Cell Biochem Biophys 2014; 68:463-73. [PMID: 24078401 DOI: 10.1007/s12013-013-9749-7] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Gastric cancer is one of the most outgoing human cancers in the world. Two main functional types were described: Intestinal adenocarcinoma and diffuse one. The most important purpose of this review is to analyze and investigate the main genetic factors involved in tumorogenesis of stomach and the molecular mechanism of their expression regulation alongside with the importance of cancer stem cells and their relationship with gastric cancer. It is evident that proper diagnosis of molecular case of cancer may lead to absolute treatment and at least reduction in the disease severity. However, stemness factors such as Sox2, Oct3/4, and Nanog were related with induced pluripotent stem cells, proposing a correlation between these stemness factors and cancer stem cells. Moreover, aberrant induction by Helicobacter pylori of the intestinal-specific homeobox transcription factors, CDX1 and CDX2, also plays an important role in this modification. There are some genes which are directly activated by CDX1 in gastric cancer and distinguished stemness-related reprogramming factors like SALL4 and KLF5. Correspondingly, we also aimed to present the main important epigenetic changes such as DNA methylation, histone modification, and chromatin modeling of stemness genes in disease development. Remarkably, a better understanding of molecular bases of cancer may lead to novel diagnostic, therapeutic, and preventive approaches by some genetic and epigenetic changes such as gene amplifications, gene silencing by DNA methylation, losses of imprinting, LOH, and mutations. Consequently, genome-wide searches of gene expression are widely important for surveying the proper mechanisms of cancer emergence and development. Conspicuously, this review explains an outline of the molecular mechanism and new approaches in gastric cancer.
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Affiliation(s)
- Haleh Akhavan-Niaki
- Cellular and Molecular Biology Research Center, Babol University of Medical Sciences, Babol, Iran
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15
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Allegra A, Alonci A, Penna G, Innao V, Gerace D, Rotondo F, Musolino C. The cancer stem cell hypothesis: a guide to potential molecular targets. Cancer Invest 2014; 32:470-95. [PMID: 25254602 DOI: 10.3109/07357907.2014.958231] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Common cancer theories hold that tumor is an uncontrolled somatic cell proliferation caused by the progressive addition of random mutations in critical genes that control cell growth. Nevertheless, various contradictions related to the mutation theory have been reported previously. These events may be elucidated by the persistence of residual tumor cells, called Cancer Stem Cells (CSCs) responsible for tumorigenesis, tumor maintenance, tumor spread, and tumor relapse. Herein, we summarize the current understanding of CSCs, with a focus on the possibility to identify specific markers of CSCs, and discuss the clinical application of targeting CSCs for cancer treatment.
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16
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Tanase CP, Neagu AI, Necula LG, Mambet C, Enciu AM, Calenic B, Cruceru ML, Albulescu R. Cancer stem cells: involvement in pancreatic cancer pathogenesis and perspectives on cancer therapeutics. World J Gastroenterol 2014; 20:10790-10801. [PMID: 25152582 PMCID: PMC4138459 DOI: 10.3748/wjg.v20.i31.10790] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 02/07/2014] [Accepted: 04/05/2014] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer is one of the most aggressive and lethal malignancies. Despite remarkable progress in understanding pancreatic carcinogenesis at the molecular level, as well as progress in new therapeutic approaches, pancreatic cancer remains a disease with a dismal prognosis. Among the mechanisms responsible for drug resistance, the most relevant are changes in individual genes or signaling pathways and the presence of highly resistant cancer stem cells (CSCs). In pancreatic cancer, CSCs represent 0.2%-0.8% of pancreatic cancer cells and are considered to be responsible for tumor growth, invasion, metastasis and recurrence. CSCs have been extensively studied as of late to identify specific surface markers to ensure reliable sorting and for signaling pathways identified to play a pivotal role in CSC self-renewal. Involvement of CSCs in pancreatic cancer pathogenesis has also highlighted these cells as the preferential targets for therapy. The present review is an update of the results in two main fields of research in pancreatic cancer, pathogenesis and therapy, focused on the narrow perspective of CSCs.
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Carrasco E, Alvarez PJ, Prados J, Melguizo C, Rama AR, Aránega A, Rodríguez-Serrano F. Cancer stem cells and their implication in breast cancer. Eur J Clin Invest 2014; 44:678-87. [PMID: 24766664 DOI: 10.1111/eci.12276] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2014] [Accepted: 04/23/2014] [Indexed: 12/13/2022]
Abstract
BACKGROUND The cancer stem cell (CSC) hypothesis on the origin of cancer has recently gained considerable support. CSCs are tumour cells with the capacity for self-renewal and differentiation that direct the origin and progression of the disease and may be responsible for relapse, metastasis and treatment failures. DESIGN This article reviews breast CSCs (BCSCs) phenotyping, clinical implications and clinical trials focused on BCSCs in breast cancer. Relevant studies were found through PubMed and Clinicaltrials.gov databases. RESULTS Cancer stem cells are identified and isolated using membrane and cell activity markers; in the case of BCSCs, these are CD44(+) /CD24(low/-) and show aldehyde dehydrogenase activity, alongside their capacity to grow and form mammospheres. The presence of stem cell properties is associated with a worse outcome. Hence, these cells have important clinical implications, and elucidation of the mechanisms underlying their activity will allow the development of novel effective therapies and diagnostic instruments, improving the prognosis of these patients. CONCLUSIONS Standard treatments are directed against the tumour mass and do not eliminate CSCs. There is therefore a need for specific anti-CSC therapies, and numerous authors are investigating new targets to this end, as reported in this review. It is also necessary for clinical trials to be undertaken to allow this new knowledge to be applied in the clinical setting. However, there have been few trials on anti-BCSCs therapies to date.
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Affiliation(s)
- E Carrasco
- Institute of Biopathology and Regenerative Medicine (IBIMER), University of Granada, Armilla, Spain; PhD Program in Biomedicine, University of Granada, Granada, Spain
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18
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Tian J, Li X, Si M, Liu T, Li J. CD271+ osteosarcoma cells display stem-like properties. PLoS One 2014; 9:e98549. [PMID: 24893164 PMCID: PMC4043643 DOI: 10.1371/journal.pone.0098549] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2013] [Accepted: 05/05/2014] [Indexed: 11/19/2022] Open
Abstract
Cancer stem cell (CSC) theory has been proposed and verified in many cancers. The existence of osteosarcoma CSCs has been confirmed for many years and multiple surface markers have been employed to identify them. In this study, we identified CD271+ subpopulation of osteosarcoma displaying stem-like properties. CD271, known as the neural crest nerve growth factor receptor, is the marker of bone marrow mesenchymal stem cells (MSCs) and human melanoma-initiating cells. We discovered that CD271 was expressed differentially in diverse types of human osteosarcoma and stabilized cell lines. CD271+ osteosarcoma cells displayed most of the properties of CSC, such as self-renewal, differentiation, drug resistance and tumorigenicity in vivo. Nanog, Oct3/4, STAT3, DNA-PKcs, Bcl-2 and ABCG2 were more expressed in CD271+ cells compared with CD271− cells. Our study supported the osteosarcoma CSC hypothesis and, to a certain extent, revealed one of the possible mechanisms involved in maintaining CSCs properties.
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Affiliation(s)
- Jiguang Tian
- Department of Orthopedics, Qilu Hospital, Shandong University, Shandong, China
| | - Xin Li
- Department of Orthopedics, Qilu Hospital, Shandong University, Shandong, China
| | - Meng Si
- Department of Orthopedics, Qilu Hospital, Shandong University, Shandong, China
| | - Ting Liu
- Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, Shandong, China
| | - Jianmin Li
- Department of Orthopedics, Qilu Hospital, Shandong University, Shandong, China
- * E-mail:
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Gammaitoni L, Leuci V, Mesiano G, Giraudo L, Todorovic M, Carnevale-Schianca F, Aglietta M, Sangiolo D. Immunotherapy of cancer stem cells in solid tumors: initial findings and future prospective. Expert Opin Biol Ther 2014; 14:1259-70. [PMID: 24835841 DOI: 10.1517/14712598.2014.918099] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
INTRODUCTION Conventional chemotherapies seemed to have reached a therapeutic plateau in the treatment of solid tumors and many metastatic diseases are still incurable. Events of chemo-resistance and relapses appear to be sustained by a subset of putative cancer stem cells (CSCs). New anticancer strategies need to face this new challenge exploring their efficacy against CSCs. Immunotherapy has raised enthusiasms in cancer therapy and its potential against CSCs is an intriguing field of research. AREAS COVERED In this work we reviewed the immunotherapy approaches directed against CSCs in solid tumors. We schematically divided adaptive immunotherapy strategies, mainly based on dendritic cell-vaccination, and strategies exploiting MHC-unrestricted effectors like natural killer cells, γδ T lymphocytes and cytokine-induced killer cells. Findings, strength and limitations of these models are discussed and compared highlighting their potential clinical relevance. EXPERT OPINION The important biologic role and clinical relevance of CSCs introduced a 'noble target' for immunotherapy and cancer treatments in general. Initial evidences suggest that CSCs may be susceptible to various types of immunotherapy attacks, overcoming their chemo-resistance. Investigation of important safety issues, based on shared features with 'normal' stem cells, along with intriguing synergisms with modulatory agents are open challenges for the next future and effective clinical translation.
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20
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Pos Z, Spivey TL, Liu H, Sommariva M, Chen J, Wunderlich JR, Parisi G, Tomei S, Ayotte BD, Stroncek DF, Malek JA, Robbins PF, Rivoltini L, Maio M, Chouchane L, Wang E, Marincola FM. Longitudinal study of recurrent metastatic melanoma cell lines underscores the individuality of cancer biology. J Invest Dermatol 2013; 134:1389-1396. [PMID: 24270663 PMCID: PMC3989423 DOI: 10.1038/jid.2013.495] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2013] [Revised: 09/22/2013] [Accepted: 10/21/2013] [Indexed: 01/15/2023]
Abstract
Recurrent metastatic melanoma provides a unique opportunity to analyze disease evolution in metastatic cancer. Here, we followed up eight patients with an unusually prolonged history of metastatic melanoma, who developed a total of 26 recurrences over several years. Cell lines derived from each metastasis were analyzed by comparative genomic hybridization and global transcript analysis. We observed that conserved, patient-specific characteristics remain stable in recurrent metastatic melanoma even after years and several recurrences. Differences among individual patients exceeded within-patient lesion variability, both at the DNA copy number (P<0.001) and RNA gene expression level (P<0.001). Conserved patient-specific traits included expression of several cancer/testis antigens and the c-kit proto-oncogene throughout multiple recurrences. Interestingly, subsequent recurrences of different patients did not display consistent or convergent changes toward a more aggressive disease phenotype. Finally, sequential recurrences of the same patient did not descend progressively from each other, as irreversible mutations such as homozygous deletions were frequently not inherited from previous metastases. This study suggests that the late evolution of metastatic melanoma, which markedly turns an indolent disease into a lethal phase, is prone to preserve case-specific traits over multiple recurrences and occurs through a series of random events that do not follow a consistent stepwise process.
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Affiliation(s)
- Zoltan Pos
- Infectious Disease and Immunogenetics Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA; Hungarian Academy of Sciences-Semmelweis University "Lendület" Experimental and Translational Immunomics Research Group, Budapest, Hungary; Department of Genetics, Cell, and Immunobiology, Semmelweis University, Budapest, Hungary
| | - Tara L Spivey
- Infectious Disease and Immunogenetics Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA; Clinical Research Training Program (CRTP), National Institutes of Health, Bethesda, Maryland, USA; Department of General Surgery, Rush University Medical Center, Chicago, Illinois, USA
| | - Hui Liu
- Infectious Disease and Immunogenetics Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA
| | - Michele Sommariva
- Infectious Disease and Immunogenetics Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA; Department of Biomedical Sciences for Health, Universita' degli Studi di Milano, Milan, Italy
| | - Jinguo Chen
- Infectious Disease and Immunogenetics Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA
| | - John R Wunderlich
- Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Giulia Parisi
- Cancer Bioimmunotherapy Unit, Centro di Riferimento Oncologico, Aviano, Italy
| | - Sara Tomei
- Department of Genetic Medicine, Weill Cornell Medical College in Qatar, Education City, Doha, Qatar
| | - Ben D Ayotte
- Department of Biology, Northern Michigan University, Marquette, Michigan, USA
| | - David F Stroncek
- Cell Processing Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA
| | - Joel A Malek
- Department of Genetic Medicine, Weill Cornell Medical College in Qatar, Education City, Doha, Qatar
| | - Paul F Robbins
- Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Licia Rivoltini
- Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Michele Maio
- Cancer Bioimmunotherapy Unit, Centro di Riferimento Oncologico, Aviano, Italy
| | - Lotfi Chouchane
- Weill Cornell Medical College in Qatar, Education City, Doha, Qatar
| | - Ena Wang
- Infectious Disease and Immunogenetics Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA
| | - Francesco M Marincola
- Infectious Disease and Immunogenetics Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA; Research Branch, Sidra Medical and Research Centre, Doha, Qatar.
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21
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Faber A, Aderhold C, Goessler UR, Hoermann K, Schultz JD, Umbreit C, Walliczek U, Stern-Straeter J. Interaction of a CD44+ head and neck squamous cell carcinoma cell line with a stromal cell-derived factor-1-expressing supportive niche: An in vitro model. Oncol Lett 2013; 7:82-86. [PMID: 24348826 PMCID: PMC3861560 DOI: 10.3892/ol.2013.1673] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2013] [Accepted: 09/19/2013] [Indexed: 01/15/2023] Open
Abstract
The cancer stem cell (CSC) theory implies that CSCs are surrounded by supportive stromal cells, which are known as the CSC niche. Stromal cell-derived factor-1 (SDF-1) shows a multitude of functional effects in head and neck squamous cell carcinoma (HNSCC) cells, including migration and polarization. Therefore, the SDF-1-CXCR4 axis may be involved in the pathophysiology of the progression, recurrence and metastasis of malignant diseases of the head and neck. In the present study, the CD44+ HNSCC UM-SCC-11A cell line was used as a model for CSCs. The interaction between the UM-SCC-11A cells and the supportive microenvironmental cells, including fibrocytes, human umbilical vein endothelial cells (HUVECs) and human microvascular vein endothelial cells (HMVECs) was evaluated. All the cell types that were tested were shown to secrete different concentrations of SDF-1 into the surrounding culture medium [mean (m)fibro, 1243.3±156.2 pg/ml; mHMVEC, 1061.4±23.2 pg/ml; mHUVEC, 849.6±110.9 pg/ml]. The migration of the UM-SCC-11A cells towards the supportive cells was increased by a higher supply of SDF-1 (contrfibro, 315.23±61.55 μm; mfibro, 477.73±143.7 μm; Pfibro=0.003; contrHMVEC, 123.41±66.68 μm; mHMVEC, 249.04±111.95 μm; PHMVEC=0.004; contrHUVEC, 189.7±93.26 μm; mHUVEC, 260.82±161.58 μm). The amount of the UM-SCC-11A cells that migrated towards the differentiated fibrocytes was significantly higher than that which migrated towards the HMVECs or HUVECs (Pfibro/HMVEC=2.12E-11; Pfibro/HUVEC=2.28E-5). Cell-cell interaction by podia formation of the UM-SCC-11A cells was observed in all the supportive cell types that were tested. Broadly based cell-cell contacts were observed. By contrast, digitiform podia formations presented by the UM-SCC-11A cells were determined using fluorescence microscopy. The SDF-1-CXCR4 axis is postulated to be a crucial pathway in the interaction between CSCs and their surrounding supportive cells. Understanding the cell-cell interactions in the CSC niche using in vitro models may aid in gaining further insight into these mechanisms and finding new strategies of therapy in this field.
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Affiliation(s)
- Anne Faber
- Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Centre Mannheim, Mannheim D-68167, Germany
| | - Christoph Aderhold
- Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Centre Mannheim, Mannheim D-68167, Germany
| | - Ulrich Reinhart Goessler
- Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Centre Mannheim, Mannheim D-68167, Germany
| | - Karl Hoermann
- Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Centre Mannheim, Mannheim D-68167, Germany
| | - Johannes David Schultz
- Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Centre Mannheim, Mannheim D-68167, Germany
| | - Claudia Umbreit
- Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Centre Mannheim, Mannheim D-68167, Germany
| | - Ute Walliczek
- Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Centre Mannheim, Mannheim D-68167, Germany
| | - Jens Stern-Straeter
- Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Centre Mannheim, Mannheim D-68167, Germany
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22
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Shen C, Xiang M, Nie C, Hu H, Ma Y, Wu H. CD44 as a molecular marker to screen cancer stem cells in hypopharyngeal cancer. Acta Otolaryngol 2013; 133:1219-26. [PMID: 23837451 DOI: 10.3109/00016489.2013.811750] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
CONCLUSIONS The CD44(+) cells have a stronger proliferative capacity and higher tumorigenic potential than the CD44(-) cells, which suggests that the cancer stem cells of hypopharyngeal cancer may exist in the CD44(+) tumor cell population. Therefore, we propose that CD44 is an important biological marker to screen cancer stem cells of hypopharyngeal cancer. OBJECTIVES To study the significance of CD44 as a molecular marker for screening cancer stem cells in hypopharyngeal cancer. METHODS The CD44 expression levels in the hypopharyngeal cancer cell line FaDu were analyzed using flow cytometry. To investigate the biological significance of the CD44(+) population, we sorted the CD44(+) and CD44(-) cell populations by using magnetic-associated cell sorting (MACS) technology. After the separation, the purity of the CD44(+) cells was determined using flow cytometry. The MTT method was used to detect the different proliferation capabilities of the CD44(+) and CD44(-) cells in vitro. The tumorigenicity of the CD44(+) and CD44(-) cells was determined by injecting CD44(+) or CD44(-) cells (1 × 10(6) and 1 × 10(5)) into the body of NOD/SCID mice. RESULTS Some (21.1 ± 1.56)% of the hypopharyngeal cancer cell line FaDu cells expressed CD44. The CD44(+) population was efficiently sorted by MACS, and after separation, the purity of the CD44(+) cells was (99.4 ± 0.29)%. The MTT assay indicated that the sorted CD44(+) cells had a stronger proliferative capacity than the CD44(-) cells. The tumorigenicity study showed that all the mice injected with 1 × 10(6) CD44(+) cells developed tumors (8/8), half the mice injected with 1 × 10(6) CD44(-) cells developed tumors (4/8), 1 of the 8 mice injected with 1 × 10(5) CD44(+) cells developed tumors (12.5%), but none of the mice injected with 1 × 10(5) CD44(-) cells developed any tumors (0/8). At the same concentration, the difference in tumorigenic rates between the CD44(+) and CD44(-) groups was statistically significant (Fisher's exact test, p < 0.05). Furthermore, the CD44(+) group had a shorter incubation period than the CD44(-) group. In addition, the average tumor volume of the CD44(+) group was (2017.81 ± 538.50) mm(3); however, the average tumor volume of the CD44(-) group was (1153.25 ± 503.18) mm(3). The difference was statistically significant (t = 2.67, p < 0.05).
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Affiliation(s)
- Chenling Shen
- Department of Otolaryngology & Head and Neck Surgery, The Ear Institute, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai , China
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23
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Eccles SA, Aboagye EO, Ali S, Anderson AS, Armes J, Berditchevski F, Blaydes JP, Brennan K, Brown NJ, Bryant HE, Bundred NJ, Burchell JM, Campbell AM, Carroll JS, Clarke RB, Coles CE, Cook GJR, Cox A, Curtin NJ, Dekker LV, dos Santos Silva I, Duffy SW, Easton DF, Eccles DM, Edwards DR, Edwards J, Evans DG, Fenlon DF, Flanagan JM, Foster C, Gallagher WM, Garcia-Closas M, Gee JMW, Gescher AJ, Goh V, Groves AM, Harvey AJ, Harvie M, Hennessy BT, Hiscox S, Holen I, Howell SJ, Howell A, Hubbard G, Hulbert-Williams N, Hunter MS, Jasani B, Jones LJ, Key TJ, Kirwan CC, Kong A, Kunkler IH, Langdon SP, Leach MO, Mann DJ, Marshall JF, Martin LA, Martin SG, Macdougall JE, Miles DW, Miller WR, Morris JR, Moss SM, Mullan P, Natrajan R, O’Connor JPB, O’Connor R, Palmieri C, Pharoah PDP, Rakha EA, Reed E, Robinson SP, Sahai E, Saxton JM, Schmid P, Smalley MJ, Speirs V, Stein R, Stingl J, Streuli CH, Tutt ANJ, Velikova G, Walker RA, Watson CJ, Williams KJ, Young LS, Thompson AM. Critical research gaps and translational priorities for the successful prevention and treatment of breast cancer. Breast Cancer Res 2013; 15:R92. [PMID: 24286369 PMCID: PMC3907091 DOI: 10.1186/bcr3493] [Citation(s) in RCA: 275] [Impact Index Per Article: 22.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2013] [Accepted: 09/12/2013] [Indexed: 02/08/2023] Open
Abstract
INTRODUCTION Breast cancer remains a significant scientific, clinical and societal challenge. This gap analysis has reviewed and critically assessed enduring issues and new challenges emerging from recent research, and proposes strategies for translating solutions into practice. METHODS More than 100 internationally recognised specialist breast cancer scientists, clinicians and healthcare professionals collaborated to address nine thematic areas: genetics, epigenetics and epidemiology; molecular pathology and cell biology; hormonal influences and endocrine therapy; imaging, detection and screening; current/novel therapies and biomarkers; drug resistance; metastasis, angiogenesis, circulating tumour cells, cancer 'stem' cells; risk and prevention; living with and managing breast cancer and its treatment. The groups developed summary papers through an iterative process which, following further appraisal from experts and patients, were melded into this summary account. RESULTS The 10 major gaps identified were: (1) understanding the functions and contextual interactions of genetic and epigenetic changes in normal breast development and during malignant transformation; (2) how to implement sustainable lifestyle changes (diet, exercise and weight) and chemopreventive strategies; (3) the need for tailored screening approaches including clinically actionable tests; (4) enhancing knowledge of molecular drivers behind breast cancer subtypes, progression and metastasis; (5) understanding the molecular mechanisms of tumour heterogeneity, dormancy, de novo or acquired resistance and how to target key nodes in these dynamic processes; (6) developing validated markers for chemosensitivity and radiosensitivity; (7) understanding the optimal duration, sequencing and rational combinations of treatment for improved personalised therapy; (8) validating multimodality imaging biomarkers for minimally invasive diagnosis and monitoring of responses in primary and metastatic disease; (9) developing interventions and support to improve the survivorship experience; (10) a continuing need for clinical material for translational research derived from normal breast, blood, primary, relapsed, metastatic and drug-resistant cancers with expert bioinformatics support to maximise its utility. The proposed infrastructural enablers include enhanced resources to support clinically relevant in vitro and in vivo tumour models; improved access to appropriate, fully annotated clinical samples; extended biomarker discovery, validation and standardisation; and facilitated cross-discipline working. CONCLUSIONS With resources to conduct further high-quality targeted research focusing on the gaps identified, increased knowledge translating into improved clinical care should be achievable within five years.
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Affiliation(s)
- Suzanne A Eccles
- The Institute of Cancer Research, 15 Cotswold Road, London SM2 5MG, UK
| | - Eric O Aboagye
- Imperial College London, Exhibition Rd, London SW7 2AZ, UK
| | - Simak Ali
- Imperial College London, Exhibition Rd, London SW7 2AZ, UK
| | | | - Jo Armes
- Kings College London, Strand, London WC2R 2LS, UK
| | | | - Jeremy P Blaydes
- University of Southampton, University Road, Southampton SO17 1BJ, UK
| | - Keith Brennan
- University of Manchester, Oxford Road, Manchester M13 9PL, UK
| | - Nicola J Brown
- University of Sheffield, Western Bank, Sheffield S10 2TN, UK
| | - Helen E Bryant
- University of Sheffield, Western Bank, Sheffield S10 2TN, UK
| | - Nigel J Bundred
- University of Manchester, Oxford Road, Manchester M13 9PL, UK
| | | | | | - Jason S Carroll
- Cancer Research UK, Cambridge Research Institute/University of Cambridge, Trinity Lane, Cambridge CB2 1TN, UK
| | - Robert B Clarke
- University of Manchester, Oxford Road, Manchester M13 9PL, UK
| | - Charlotte E Coles
- Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge CB2 0QQ, UK
| | - Gary JR Cook
- Kings College London, Strand, London WC2R 2LS, UK
| | - Angela Cox
- University of Sheffield, Western Bank, Sheffield S10 2TN, UK
| | - Nicola J Curtin
- Newcastle University, Claremont Road, Newcastle upon Tyne NE1 7RU, UK
| | | | | | - Stephen W Duffy
- Queen Mary University of London, Mile End Road, London E1 4NS, UK
| | - Douglas F Easton
- Cancer Research UK, Cambridge Research Institute/University of Cambridge, Trinity Lane, Cambridge CB2 1TN, UK
| | - Diana M Eccles
- University of Southampton, University Road, Southampton SO17 1BJ, UK
| | - Dylan R Edwards
- University of East Anglia, Earlham Road, Norwich NR4 7TJ, UK
| | - Joanne Edwards
- University of Glasgow, University Avenue, Glasgow G12 8QQ, UK
| | - D Gareth Evans
- University of Manchester, Oxford Road, Manchester M13 9PL, UK
| | - Deborah F Fenlon
- University of Southampton, University Road, Southampton SO17 1BJ, UK
| | | | - Claire Foster
- University of Southampton, University Road, Southampton SO17 1BJ, UK
| | | | | | - Julia M W Gee
- University of Cardiff, Park Place, Cardiff CF10 3AT, UK
| | - Andy J Gescher
- University of Leicester, University Road, Leicester LE1 4RH, UK
| | - Vicky Goh
- Kings College London, Strand, London WC2R 2LS, UK
| | - Ashley M Groves
- University College London, Gower Street, London WC1E 6BT, UK
| | | | - Michelle Harvie
- University of Manchester, Oxford Road, Manchester M13 9PL, UK
| | - Bryan T Hennessy
- Royal College of Surgeons Ireland, 123, St Stephen’s Green, Dublin 2, Ireland
| | | | - Ingunn Holen
- University of Sheffield, Western Bank, Sheffield S10 2TN, UK
| | - Sacha J Howell
- University of Manchester, Oxford Road, Manchester M13 9PL, UK
| | - Anthony Howell
- University of Manchester, Oxford Road, Manchester M13 9PL, UK
| | | | | | | | - Bharat Jasani
- University of Cardiff, Park Place, Cardiff CF10 3AT, UK
| | - Louise J Jones
- Queen Mary University of London, Mile End Road, London E1 4NS, UK
| | - Timothy J Key
- University of Oxford, Wellington Square, Oxford OX1 2JD, UK
| | - Cliona C Kirwan
- University of Manchester, Oxford Road, Manchester M13 9PL, UK
| | - Anthony Kong
- University of Oxford, Wellington Square, Oxford OX1 2JD, UK
| | - Ian H Kunkler
- University of Edinburgh, South Bridge, Edinburgh EH8 9YL, UK
| | - Simon P Langdon
- University of Edinburgh, South Bridge, Edinburgh EH8 9YL, UK
| | - Martin O Leach
- The Institute of Cancer Research, 15 Cotswold Road, London SM2 5MG, UK
| | - David J Mann
- Imperial College London, Exhibition Rd, London SW7 2AZ, UK
| | - John F Marshall
- Queen Mary University of London, Mile End Road, London E1 4NS, UK
| | - Lesley Ann Martin
- The Institute of Cancer Research, 15 Cotswold Road, London SM2 5MG, UK
| | - Stewart G Martin
- University of Nottingham, University Park, Nottingham NG7 2RD, UK
| | | | | | | | | | - Sue M Moss
- Queen Mary University of London, Mile End Road, London E1 4NS, UK
| | - Paul Mullan
- Queen’s University Belfast, University Road, Belfast BT7 1NN, UK
| | - Rachel Natrajan
- The Institute of Cancer Research, 15 Cotswold Road, London SM2 5MG, UK
| | | | | | - Carlo Palmieri
- The University of Liverpool, Brownlow Hill, Liverpool L69 7ZX, UK
| | - Paul D P Pharoah
- Cancer Research UK, Cambridge Research Institute/University of Cambridge, Trinity Lane, Cambridge CB2 1TN, UK
| | - Emad A Rakha
- University of Nottingham, University Park, Nottingham NG7 2RD, UK
| | - Elizabeth Reed
- Princess Alice Hospice, West End Lane, Esher KT10 8NA, UK
| | - Simon P Robinson
- The Institute of Cancer Research, 15 Cotswold Road, London SM2 5MG, UK
| | - Erik Sahai
- London Research Institute, 44 Lincoln’s Inn Fields, London WC2A 3LY, UK
| | - John M Saxton
- University of East Anglia, Earlham Road, Norwich NR4 7TJ, UK
| | - Peter Schmid
- Brighton and Sussex Medical School, University of Sussex, Brighton, East Sussex BN1 9PX, UK
| | | | | | - Robert Stein
- University College London, Gower Street, London WC1E 6BT, UK
| | - John Stingl
- Cancer Research UK, Cambridge Research Institute/University of Cambridge, Trinity Lane, Cambridge CB2 1TN, UK
| | | | | | | | | | - Christine J Watson
- Cancer Research UK, Cambridge Research Institute/University of Cambridge, Trinity Lane, Cambridge CB2 1TN, UK
| | - Kaye J Williams
- University of Manchester, Oxford Road, Manchester M13 9PL, UK
| | - Leonie S Young
- Royal College of Surgeons Ireland, 123, St Stephen’s Green, Dublin 2, Ireland
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Pizon M, Zimon D, Carl S, Pachmann U, Pachmann K, Camara O. Heterogeneity of circulating epithelial tumour cells from individual patients with respect to expression profiles and clonal growth (sphere formation) in breast cancer. Ecancermedicalscience 2013; 7:343. [PMID: 23983815 PMCID: PMC3750196 DOI: 10.3332/ecancer.2013.343] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2013] [Indexed: 01/16/2023] Open
Abstract
Background The detection of tumour cells circulating in the peripheral blood of patients with breast cancer is a sign that cells have been able to leave the primary tumour and survive in the circulation. However, in order to form metastases, they require additional properties such as the ability to adhere, self-renew, and grow. Here we present data that a variable fraction among the circulating tumour cells detected by the Maintrac® approach expresses mRNA of the stem cell gene NANOG and of the adhesion molecule vimentin and is capable of forming tumour spheres, a property ascribed to tumour-initiating cells (TICs). Patients and methods Between ten and 50 circulating epithelial antigen-positive cells detected by the Maintrac approach were selected randomly from each of 20 patients with breast cancer before and after surgery and were isolated using automated capillary aspiration and deposited individually onto slides for expression profiling. In addition, the circulating tumour cells were cultured without isolation among the white blood cells from 39 patients with breast cancer in different stages of disease using culture methods favouring growth of epithelial cells. Results Although no epithelial cell adhesion molecule (EpCAM)-positive cells expressing stem cell genes or the adhesion molecule vimentin was detected before surgery, 10%–20% of the cells were found to be positive for mRNA of these genes after surgery. Tumour spheres from circulating cells of 39 patients with different stages of breast cancer were grown without previous isolation in a fraction increasing with the aggressivity of the tumour. Summary Here we show that among the peripherally circulating tumour cells, a variable fraction is able to express stem cell and adhesion properties and can be grown into tumour spheres, a property ascribed to cells capable of initiating tumours and metastases.
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Affiliation(s)
- M Pizon
- Transfusion Center Bayreuth D-95448, Germany
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FABER ANNE, GOESSLER ULRICHREINHART, HOERMANN KARL, SCHULTZ JOHANNESDAVID, UMBREIT CLAUDIA, STERN-STRAETER JENS. SDF-1-CXCR4 axis: Cell trafficking in the cancer stem cell niche of head and neck squamous cell carcinoma. Oncol Rep 2013; 29:2325-31. [DOI: 10.3892/or.2013.2380] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2012] [Accepted: 12/17/2012] [Indexed: 11/06/2022] Open
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Faber A, Hoermann K, Stern-Straeter J, Schultz DJ, Goessler UR. Functional effects of SDF-1α on a CD44(+) CXCR4(+) squamous cell carcinoma cell line as a model for interactions in the cancer stem cell niche. Oncol Rep 2012; 29:579-84. [PMID: 23232503 DOI: 10.3892/or.2012.2171] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2012] [Accepted: 10/05/2012] [Indexed: 11/06/2022] Open
Abstract
Stromal cell-derived factor-1α (SDF-1α), also known as CXCL12, has variable effects on a plurality of cells. It is known to have selective effects on cell migration, morphology, survival and cell homing. As such the SDF-1-CXCR4 axis is postulated to be a crucial key pathway in the interaction between (cancer) stem cells and their surrounding supportive cells, the so-called (cancer) stem cell niche. We evaluated the expression of CD44 as a cancer stem cell (CSC) marker and the expression of CXCR4 in the head and neck squamous cell carcinoma (HNSCC) cell line UM-SCC 11A. In addition, we monitored proliferation, formation of podia and migration of UM-SCC 11A cells under the influence of SDF-1α. Whereas SDF-1α induced the formation of podia of CD44(+) CXCR4(+) UM-SCC 11A cells in a dose-dependent manner and the maximum number of cells exhibiting the formation of podia was observed under the influence of 10 ng/ml SDF-1α (P=5.3x10(-6)), the highest number of migrating cells was noted using a concentration of 100 ng/ml (P=0.027). Proliferation and survival were not affected by SDF-1α. We showed that UM-SCC 11A cells could be a target for SDF-1α by CXCR4 expression and these cells also showed characteristics of HNSCC CSCs via CD44 expression. We demonstrated that SDF-1α is a chemoattractant for UM-SCC 11A cells, and a maximum directed migration was achieved under the influence of 100 ng/ml SDF-1α. Changes in cell morphology by presenting filopodia or a prominent uropod were noted following treatment of 10 ng/ml SDF-1α. The SDF-CXCR4 axis may play a crucial role in the interaction between CSCs and their supportive cells in the CSC niche. Understanding these interactions may help to gain further insight into the pathophysiology of the progression and recurrence of malignant diseases and thus help to develop novel strategies for therapy.
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Affiliation(s)
- Anne Faber
- Department of Otorhinolaryngology Head and Neck Surgery, University Medical Centre Mannheim, 68167 Mannheim, Germany.
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