Integrin α6 (CD49f), The Microenvironment and Cancer Stem Cells

Author(s): Gabriele D. Bigoni-Ordóñez , Daniel Czarnowski , Tyler Parsons , Gerard J. Madlambayan* , Luis G. Villa-Diaz* .

Journal Name: Current Stem Cell Research & Therapy

Volume 14 , Issue 5 , 2019

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Cancer is a highly prevalent and potentially terminal disease that affects millions of individuals worldwide. Here, we review the literature exploring the intricacies of stem cells bearing tumorigenic characteristics and collect evidence demonstrating the importance of integrin α6 (ITGA6, also known as CD49f) in cancer stem cell (CSC) activity. ITGA6 is commonly used to identify CSC populations in various tissues and plays an important role sustaining the self-renewal of CSCs by interconnecting them with the tumorigenic microenvironment.

Keywords: Cancer stem cells, tumor microenvironment, integrin α6, laminins, self-renewal, cell signalling.

Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J Clin 2017; 67(1): 7-30.
Hanahan D, Weinberg RA. Hallmarks of cancer: The next generation. Cell 2011; 144(5): 646-74.
Meacham CE, Morrison SJ. Tumour heterogeneity and cancer cell plasticity. Nature 2013; 501(7467): 328-37.
Marusyk A, Polyak K. Tumor heterogeneity: Causes and consequences. Biochim Biophys Acta 2010; 1805(1): 105-17.
Li Y, Kong D, Ahmad A, Bao B, Sarkar FH. Pancreatic cancer stem cells: emerging target for designing novel therapy. Cancer Lett 2013; 338(1): 94-100.
Yu Y, Ramena G, Elble RC. The role of cancer stem cells in relapse of solid tumors. Front Biosci (Elite Ed) 2012; 4: 1528-41.
Kelly PN, Dakic A, Adams JM, Nutt SL, Strasser A. Tumor growth need not be driven by rare cancer stem cells. Science 2007; 317(5836): 337.
Boiko AD, Razorenova OV, van de Rijn M, et al. Human melanoma-initiating cells express neural crest nerve growth factor receptor CD271. Nature 2010; 466(7302): 133-7.
Duru N, Gernapudi R, Lo PK, et al. Characterization of the CD49f+/CD44+/CD24- single-cell derived stem cell population in basal-like DCIS cells. Oncotarget 2016; 7(30): 47511-25.
Dalerba P, Cho RW, Clarke MF. Cancer stem cells: Models and concepts. Annu Rev Med 2007; 58: 267-84.
Liu A, Yu X, Liu S. Pluripotency transcription factors and cancer stem cells: small genes make a big difference. Chin J Cancer 2013; 32(9): 483-7.
Daley GQ. Stem cells and the evolving notion of cellular identity Philos Trans R Soc Lond B Biol Sci 2015; 370(1680): 20140376
Vapniarsky N, Arzi B, Hu JC, Nolta JA, Athanasiou KA. Concise review: Human dermis as an autologous source of stem cells for tissue engineering and regenerative medicine. Stem Cells Transl Med 2015; 4(10): 1187-98.
Clevers H. The cancer stem cell: Premises, promises and challenges. Nat Med 2011; 17(3): 313-9.
Matsui WH. Cancer stem cell signaling pathways. Medicine (Baltimore) 2016; 95(1)(Suppl. 1): S8-S19.
Fuchs E, Tumbar T, Guasch G. Socializing with the neighbors: stem cells and their niche. Cell 2004; 116(6): 769-78.
Jordahl JH, Villa-Diaz L, Krebsbach PH, Lahann J. Engineered Human Stem Cell Microenvironments. Curr Stem Cell Rep 2016; 2(1): 73-84.
Hynes RO. Integrins: bidirectional, allosteric signaling machines. Cell 2002; 110(6): 673-87.
Huntsman HD, Bat T, Cheng H, et al. Human hematopoietic stem cells from mobilized peripheral blood can be purified based on CD49f integrin expression. Blood 2015; 126(13): 1631-3.
Song J, Ding FR, Li S, Li W, Li N, Xue K. CD24 and CD49f expressions of E14.5 mouse mammary anlagen cells defines putative distribution of earlier embryonic mammary stem cell activities. Biochem Cell Biol 2018; 96(5): 539-47.
Ono M, Kajitani T, Uchida H, et al. CD34 and CD49f double-positive and lineage marker-negative cells isolated from human myometrium exhibit stem cell-like properties involved in pregnancy-induced uterine remodeling. Biol Reprod 2015; 93(2): 37.
Yang Z, Dong P, Fu X, et al. CD49f Acts as an inflammation sensor to regulate differentiation, adhesion, and migration of human mesenchymal stem Cells. Stem Cells 2015; 33(9): 2798-810.
Krebsbach PH, Villa-Diaz LG. The Role of Integrin alpha6 (CD49f) in Stem Cells: More than a Conserved Biomarker. Stem Cells Dev 2017; 26(15): 1090-9.
Villa-Diaz LG, Kim JK, Laperle A, Palecek SP, Krebsbach PH. Inhibition of focal adhesion kinase signaling by integrin alpha6beta1 supports human pluripotent stem cell self-renewal. Stem Cells 2016; 34(7): 1753-64.
Zheng L, Zhu H, Mu H, et al. CD49f promotes proliferation of male dairy goat germline stem cells. Cell Prolif 2016; 49(1): 27-35.
Notta F, Doulatov S, Laurenti E, Poeppl A, Jurisica I, Dick JE. Isolation of single human hematopoietic stem cells capable of long-term multilineage engraftment. Science 2011; 333(6039): 218-21.
Ghebeh H, Sleiman GM, Manogaran PS, et al. Profiling of normal and malignant breast tissue show CD44high/CD24low phenotype as a predominant stem/progenitor marker when used in combination with Ep-CAM/CD49f markers. BMC Cancer 2013; 13: 289.
Vieira AF, Ricardo S, Ablett MP, Dionisio MR, Mendes N, Albergaria A, et al. P-cadherin is coexpressed with CD44 and CD49f and mediates stem cell properties in basal-like breast cancer. Stem Cells 2012; 30(5): 854-64.
Zhao R, Quaroni L, Casson AG. Identification and characterization of stemlike cells in human esophageal adenocarcinoma and normal epithelial cell lines. J Thorac Cardiovasc Surg 2012; 144(5): 1192-9.
Lathia JD, Gallagher J, Heddleston JM, et al. Integrin alpha 6 regulates glioblastoma stem cells. Cell Stem Cell 2010; 6(5): 421-32.
Rountree CB, Senadheera S, Mato JM, Crooks GM, Lu SC. Expansion of liver cancer stem cells during aging in methionine adenosyltransferase 1A-deficient mice. Hepatology 2008; 47(4): 1288-97.
Chan RW, Ng EH, Yeung WS. Identification of cells with colony-forming activity, self-renewal capacity, and multipotency in ovarian endometriosis. Am J Pathol 2011; 178(6): 2832-44.
Mulholland DJ, Xin L, Morim A, Lawson D, Witte O, Wu H. Lin-Sca-1+CD49fhigh stem/progenitors are tumor-initiating cells in the Pten-null prostate cancer model. Cancer Res 2009; 69(22): 8555-62.
Hoogland AM, Verhoef EI, Roobol MJ, et al. Validation of stem cell markers in clinical prostate cancer: alpha6-integrin is predictive for non-aggressive disease. Prostate 2014; 74(5): 488-96.
Schober M, Fuchs E. Tumor-initiating stem cells of squamous cell carcinomas and their control by TGF-beta and integrin/focal adhesion kinase (FAK) signaling. Proc Natl Acad Sci USA 2011; 108(26): 10544-9.
Hynes RO. Integrins: versatility, modulation, and signaling in cell adhesion. Cell 1992; 69(1): 11-25.
Lapidot T, Sirard C, Vormoor J, et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 1994; 367(6464): 645-8.
Ignatova TN, Kukekov VG, Laywell ED, Suslov ON, Vrionis FD, Steindler DA. Human cortical glial tumors contain neural stem-like cells expressing astroglial and neuronal markers in vitro. Glia 2002; 39(3): 193-206.
Hemmati HD, Nakano I, Lazareff JA, et al. Cancerous stem cells can arise from pediatric brain tumors. Proc Natl Acad Sci USA 2003; 100(25): 15178-83.
Singh SK, Hawkins C, Clarke ID, et al. Identification of human brain tumour initiating cells. Nature 2004; 432(7015): 396-401.
Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 2003; 100(7): 3983-8.
Kreso A, O’Brien CA, van Galen P, et al. Variable clonal repopulation dynamics influence chemotherapy response in colorectal cancer. Science 2013; 339(6119): 543-8.
Smalley M, Ashworth A. Stem cells and breast cancer: A field in transit. Nat Rev Cancer 2003; 3(11): 832-44.
Fillmore CM, Kuperwasser C. Human breast cancer cell lines contain stem-like cells that self-renew, give rise to phenotypically diverse progeny and survive chemotherapy. Breast Cancer Res 2008; 10(2): R25.
Hope KJ, Jin L, Dick JE. Acute myeloid leukemia originates from a hierarchy of leukemic stem cell classes that differ in self-renewal capacity. Nat Immunol 2004; 5(7): 738-43.
Kucia M, Ratajczak MZ. Stem cells as a two edged sword--from regeneration to tumor formation. J Physiol Pharmacol 2006; 57(Suppl. 7): 5-16.
White RA, Neiman JM, Reddi A, et al. Epithelial stem cell mutations that promote squamous cell carcinoma metastasis. J Clin Invest 2013; 123(10): 4390-404.
Ngalame NN, Tokar EJ, Person RJ, Xu Y, Waalkes MP. Aberrant microRNA expression likely controls RAS oncogene activation during malignant transformation of human prostate epithelial and stem cells by arsenic. Toxicol Sci 2014; 138(2): 268-77.
Krivtsov AV, Twomey D, Feng Z, et al. Transformation from committed progenitor to leukaemia stem cell initiated by MLL-AF9. Nature 2006; 442(7104): 818-22.
Jamieson CH, Ailles LE, Dylla SJ, et al. Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N Engl J Med 2004; 351(7): 657-67.
Morel AP, Lievre M, Thomas C, Hinkal G, Ansieau S, Puisieux A. Generation of breast cancer stem cells through epithelial-mesenchymal transition. PLoS One 2008; 3(8)e2888
Biddle A, Mackenzie IC. Cancer stem cells and EMT in carcinoma. Cancer Metastasis Rev 2012. [Epub ahead of print].
Mani SA, Guo W, Liao MJ, et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 2008; 133(4): 704-15.
Morrison SJ, Kimble J. Asymmetric and symmetric stem-cell divisions in development and cancer. Nature 2006; 441(7097): 1068-74.
Bajaj J, Zimdahl B, Reya T. Fearful symmetry: Subversion of asymmetric division in cancer development and progression. Cancer Res 2015; 75(5): 792-7.
Al-Hajj M, Clarke MF. Self-renewal and solid tumor stem cells. Oncogene 2004; 23(43): 7274-82.
Knoblich JA. Asymmetric cell division: Recent developments and their implications for tumour biology. Nat Rev Mol Cell Biol 2010; 11(12): 849-60.
Xin T, Greco V, Myung P. Hardwiring Stem Cell Communication through Tissue Structure. Cell 2016; 164(6): 1212-25.
Oh M, Nor JE. The Perivascular Niche and Self-Renewal of Stem Cells. Front Physiol 2015; 6: 367.
Fujisaki J, Wu J, Carlson AL, et al. In vivo imaging of Treg cells providing immune privilege to the haematopoietic stem-cell niche. Nature 2011; 474(7350): 216-9.
Watt FM, Huck WT. Role of the extracellular matrix in regulating stem cell fate. Nat Rev Mol Cell Biol 2013; 14(8): 467-73.
Mohyeldin A, Garzon-Muvdi T, Quinones-Hinojosa A. Oxygen in stem cell biology: A critical component of the stem cell niche. Cell Stem Cell 2010; 7(2): 150-61.
Kane JL, Krueger SA, Hanna A, et al. Effect of Irradiation on Tumor Microenvironment and Bone Marrow Cell Migration in a Preclinical Tumor Model. Int J Radiat Oncol Biol Phys 2016; 96(1): 170-8.
Belli C, Trapani D, Viale G, et al. Targeting the microenvironment in solid tumors. Cancer Treat Rev 2018; 65: 22-32.
Hanahan D, Coussens LM. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell 2012; 21(3): 309-22.
Folkman J. Tumor angiogenesis. Adv Cancer Res 1974; 19(0): 331-58.
Ferreira SC Jr, Martins ML, Vilela MJ. Reaction-diffusion model for the growth of avascular tumor. Phys Rev E Stat Nonlin Soft Matter Phys 2002; 65(2 Pt 1)021907
Bergers G, Benjamin LE. Tumorigenesis and the angiogenic switch. Nat Rev Cancer 2003; 3(6): 401-10.
Bickel ST, Juliano JD, Nagy JD. Evolution of proliferation and the angiogenic switch in tumors with high clonal diversity. PLoS One 2014; 9(4)e91992
Baeriswyl V, Christofori G. The angiogenic switch in carcinogenesis. Semin Cancer Biol 2009; 19(5): 329-37.
Liu R, Wei S, Chen J, Xu S. Mesenchymal stem cells in lung cancer tumor microenvironment: their biological properties, influence on tumor growth and therapeutic implications. Cancer Lett 2014; 353(2): 145-52.
Peitzsch C, Perrin R, Hill RP, Dubrovska A, Kurth I. Hypoxia as a biomarker for radioresistant cancer stem cells. Int J Radiat Biol 2014; 90(8): 636-52.
Rankin EB, Giaccia AJ. The role of hypoxia-inducible factors in tumorigenesis. Cell Death Differ 2008; 15(4): 678-85.
Croci DO, Mendez-Huergo SP, Cerliani JP, Rabinovich GA. Immune-Mediated and Hypoxia-Regulated Programs: Accomplices in Resistance to Anti-angiogenic Therapies. Handb Exp Pharmacol 2017.
Brooks DL, Schwab LP, Krutilina R, et al. ITGA6 is directly regulated by hypoxia-inducible factors and enriches for cancer stem cell activity and invasion in metastatic breast cancer models. Mol Cancer 2016; 15: 26.
Petrova V, Annicchiarico-Petruzzelli M, Melino G, Amelio I. The hypoxic tumour microenvironment. Oncogenesis 2018; 7(1): 10.
Cirri P, Chiarugi P. Cancer associated fibroblasts: the dark side of the coin. Am J Cancer Res 2011; 1(4): 482-97.
Rasanen K, Vaheri A. Activation of fibroblasts in cancer stroma. Exp Cell Res 2010; 316(17): 2713-22.
Liu Y, Cao X. The origin and function of tumor-associated macrophages. Cell Mol Immunol 2015; 12(1): 1-4.
Mantovani A, Locati M. Tumor-associated macrophages as a paradigm of macrophage plasticity, diversity, and polarization: lessons and open questions. Arterioscler Thromb Vasc Biol 2013; 33(7): 1478-83.
Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. Nat Med 2013; 19(11): 1423-37.
Tjomsland V, Niklasson L, Sandstrom P, Borch K, Druid H, Bratthall C, et al. The desmoplastic stroma plays an essential role in the accumulation and modulation of infiltrated immune cells in pancreatic adenocarcinoma. Clin Dev Immunol 2011; 2011212810
Whatcott CJ, Posner RG, Von Hoff DD, Han H. Desmoplasia and chemoresistance in pancreatic cancer. In: Grippo PJ, Munshi HG, editors.Pancreatic Cancer and Tumor Microenvironment. Trivandrum, India 2012.
Aumailley M, Smyth N. The role of laminins in basement membrane function. J Anat 1998; 193(Pt 1): 1-21.
Govaere O, Wouters J, Petz M, et al. Laminin-332 sustains chemoresistance and quiescence as part of the human hepatic cancer stem cell niche. J Hepatol 2016; 64(3): 609-17.
Giannelli G, Azzariti A, Fransvea E, Porcelli L, Antonaci S, Paradiso A. Laminin-5 offsets the efficacy of gefitinib (‘Iressa’) in hepatocellular carcinoma cells. Br J Cancer 2004; 91(11): 1964-9.
Lathia JD, Li M, Hall PE, et al. Laminin alpha 2 enables glioblastoma stem cell growth. Ann Neurol 2012; 72(5): 766-78.
Ma NK, Lim JK, Leong MF, et al. Collaboration of 3D context and extracellular matrix in the development of glioma stemness in a 3D model. Biomaterials 2016; 78: 62-73.
Chang C, Goel HL, Gao H, et al. A laminin 511 matrix is regulated by TAZ and functions as the ligand for the alpha6Bbeta1 integrin to sustain breast cancer stem cells. Genes Dev 2015; 29(1): 1-6.
Seftor RE, Seftor EA, Koshikawa N, et al. Cooperative interactions of laminin 5 gamma2 chain, matrix metalloproteinase-2, and membrane type-1-matrix/metalloproteinase are required for mimicry of embryonic vasculogenesis by aggressive melanoma. Cancer Res 2001; 61(17): 6322-7.
Maniotis AJ, Folberg R, Hess A, et al. Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry. Am J Pathol 1999; 155(3): 739-52.
Watt FM. Role of integrins in regulating epidermal adhesion, growth and differentiation. EMBO J 2002; 21(15): 3919-26.
Ortiz-Sanchez E, Santiago-Lopez L, Cruz-Dominguez VB, et al. Characterization of cervical cancer stem cell-like cells: phenotyping, stemness, and human papilloma virus co-receptor expression. Oncotarget 2016; 7(22): 31943-54.
Lopez J, Poitevin A, Mendoza-Martinez V, Perez-Plasencia C, Garcia-Carranca A. Cancer-initiating cells derived from established cervical cell lines exhibit stem-cell markers and increased radioresistance. BMC Cancer 2012; 12: 48.
Haraguchi N, Ishii H, Mimori K, et al. CD49f-positive cell population efficiently enriches colon cancer-initiating cells. Int J Oncol 2013; 43(2): 425-30.
Cariati M, Naderi A, Brown JP, et al. Alpha-6 integrin is necessary for the tumourigenicity of a stem cell-like subpopulation within the MCF7 breast cancer cell line. Int J Cancer 2008; 122(2): 298-304.
Goel HL, Gritsko T, Pursell B, et al. Regulated splicing of the alpha6 integrin cytoplasmic domain determines the fate of breast cancer stem cells. Cell Rep 2014; 7(3): 747-61.
Ye F, Zhong X, Qiu Y, et al. CD49f Can Act as a Biomarker for Local or Distant Recurrence in Breast Cancer. J Breast Cancer 2017; 20(2): 142-9.
Gomez-Miragaya J, Gonzalez-Suarez E. Tumor-initiating CD49f cells are a hallmark of chemoresistant triple negative breast cancer. Mol Cell Oncol 2017; 4(4)e1338208
Ammothumkandy A, Maliekal TT, Bose MV, et al. CD66 and CD49f expressing cells are associated with distinct neoplastic phenotypes and progression in human cervical cancer. Eur J Cancer 2016; 60: 166-78.
Yamakawa N, Kaneda K, Saito Y, Ichihara E, Morishita K. The increased expression of integrin alpha6 (ITGA6) enhances drug resistance in EVI1 (high) leukemia. PLoS One 2012; 7(1)e30706
Yeung CCS, Radich J. Predicting Chemotherapy Resistance in AML. Curr Hematol Malig Rep 2017; 12(6): 530-6.
Bonardi F, Fusetti F, Deelen P, van Gosliga D, Vellenga E, Schuringa JJ. A proteomics and transcriptomics approach to identify leukemic stem cell (LSC) markers. Mol Cell Proteomics 2013; 12(3): 626-37.
Fukamachi H, Seol HS, Shimada S, et al. CD49f(high) cells retain sphere-forming and tumor-initiating activities in human gastric tumors. PLoS One 2013; 8(8)e72438
Penfornis P, Cai DZ, Harris MR, et al. High CD49f expression is associated with osteosarcoma tumor progression: a study using patient-derived primary cell cultures. Cancer Med 2014; 3(4): 796-811.
Yamamoto H, Masters JR, Dasgupta P, et al. CD49f is an efficient marker of monolayer- and spheroid colony-forming cells of the benign and malignant human prostate. PLoS One 2012; 7(10)e46979

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Year: 2019
Page: [428 - 436]
Pages: 9
DOI: 10.2174/1574888X13666181002151330
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