Integrin alpha 6: a novel therapeutic target in esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC), the most common subtype of esophageal cancer in East Asian countries, is a devastating disease characterized by distinctly high incidence and mortality rates. Our previous expression profile analysis showed that integrin alpha 6 (ITGA6) is highly expressed in ESCC tissues. To validate cell surface expression of ITGA6 as a novel target in ESCC, we investigated ITGA6 expression in tumor tissue samples and cell lines of ESCC and found that ITGA6 was upregulated in these cells. In vitro knockdown of ITGA6 in ESCC cells resulted in inhibition of cell proliferation, invasion and colony formation. In addition, we demonstrated that ITGA6 associates with integrin beta 4 (ITGB4), and that this heterodimer complex is upregulated in both ESCC tissues and cell lines. Moreover, our biodistribution results in an ESCC xenograft model indicated that ITGA6 is a possible target for antibody-related diagnostic and therapeutic modalities in ESCC. Thus, our findings suggest that ITGA6 plays an important role in tumorigenesis in ESCC and represents a potential therapeutic target in the treatment of ESCC.

[1]  P. Yu,et al.  Neoadjuvant chemotherapy for resectable esophageal carcinoma: a meta-analysis of randomized clinical trials. , 2012, Asian Pacific journal of cancer prevention : APJCP.

[2]  M. Kranzfelder,et al.  Meta‐analysis of neoadjuvant treatment modalities and definitive non‐surgical therapy for oesophageal squamous cell cancer , 2011, The British journal of surgery.

[3]  E. J. Lee,et al.  Effect of β4 Integrin Knockdown by RNA Interference in Anaplastic Thyroid Carcinoma , 2010 .

[4]  R. McLendon,et al.  Integrin alpha 6 regulates glioblastoma stem cells. , 2010, Cell stem cell.

[5]  J. Beaulieu.  Integrin α6β4 in colorectal cancer. , 2010, World journal of gastrointestinal pathophysiology.

[6]  F. J. Ramos,et al.  Anti-epidermal growth factor receptor monoclonal antibodies in cancer treatment. , 2009, Cancer treatment reviews.

[7]  B. Garmy-Susini,et al.  Integrins in angiogenesis and lymphangiogenesis , 2008, Nature Reviews Cancer.

[8]  A. Richardson,et al.  CD151 accelerates breast cancer by regulating alpha 6 integrin function, signaling, and molecular organization. , 2008, Cancer research.

[9]  K. O’Connor,et al.  Integrin α6β4 Promotes Migration, Invasion through Tiam1 Upregulation, and Subsequent , 2008 .

[10]  M. Scully,et al.  The Role of Integrins in Cancer and the Development of Anti-Integrin Therapeutic Agents for Cancer Therapy , 2008, Perspectives in medicinal chemistry.

[11]  Carlos Caldas,et al.  Alpha‐6 integrin is necessary for the tumourigenicity of a stem cell‐like subpopulation within the MCF7 breast cancer cell line , 2008, International journal of cancer.

[12]  A. Sacchi,et al.  Involvement of α6β4 integrin in the mechanisms that regulate breast cancer progression , 2007, Breast Cancer Research.

[13]  F. Carleo.  The role of lymphadenectomy in esophageal cancer. , 2005, Rays.

[14]  W. Tew,et al.  Targeted therapies for esophageal cancer. , 2005, The oncologist.

[15]  R. Hwang,et al.  The role of integrins in tumor angiogenesis. , 2004, Hematology/oncology clinics of North America.

[16]  A. Mercurio,et al.  Contributions of the alpha6 integrins to breast carcinoma survival and progression. , 2004, Molecules and cells.

[17]  Guido Tarone,et al.  Positional control of cell fate through joint integrin/receptor protein kinase signaling. , 2003, Annual review of cell and developmental biology.

[18]  J. Su,et al.  Expression of focal adhesion kinase and α5 and β1 integrins in carcinomas and its clinical significance , 2002 .

[19]  S. Law,et al.  Profiling of differentially expressed cancer-related genes in esophageal squamous cell carcinoma (ESCC) using human cancer cDNA arrays: overexpression of oncogene MET correlates with tumor differentiation in ESCC. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[20]  I. Rabinovitz,et al.  Towards a mechanistic understanding of tumor invasion--lessons from the alpha6beta 4 integrin. , 2001, Seminars in cancer biology.

[21]  G. Mizejewski,et al.  Role of integrins in cancer: survey of expression patterns. , 1999, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[22]  L. Shaw,et al.  The integrin alpha 6 beta 1 promotes the survival of metastatic human breast carcinoma cells in mice. , 1997, The American journal of pathology.

[23]  R. Juliano,et al.  Integrin alpha 5 beta 1 expression negatively regulates cell growth: reversal by attachment to fibronectin. , 1995, Molecular biology of the cell.

[24]  K. Friedrichs,et al.  High expression level of alpha 6 integrin in human breast carcinoma is correlated with reduced survival. , 1995, Cancer research.

[25]  Richard O. Hynes,et al.  Integrins: Versatility, modulation, and signaling in cell adhesion , 1992, Cell.

[26]  A. Sonnenberg,et al.  Association of the VLA alpha 6 subunit with a novel protein. A possible alternative to the common VLA beta 1 subunit on certain cell lines. , 1989, The Journal of biological chemistry.

[27]  A. Jemal,et al.  Global Cancer Statistics , 2011 .

[28]  E. J. Lee,et al.  Effect of {beta}4 integrin knockdown by RNA interference in anaplastic thyroid carcinoma. , 2010, Anticancer research.

[29]  Young-Joon Kim,et al.  Expression patterns of aurora kinase B, heat shock protein 47, and periostin in esophageal squamous cell carcinoma. , 2009, Oncology Research.

[30]  Z. Cruz-Monserrate,et al.  Integrin alpha 6 beta 4 promotes migration, invasion through Tiam1 upregulation, and subsequent Rac activation. , 2008, Neoplasia.

[31]  F.R.C.S.Ed. F.C.S.H.K. F.H.K.A.M. Philip W. Y. Chiu M.B.Ch.B.,et al.  Multicenter prospective randomized trial comparing standard esophagectomy with chemoradiotherapy for treatment of squamous esophageal cancer: Early results from the Chinese University Research Group for Esophageal Cancer (CURE) , 2007, Journal of Gastrointestinal Surgery.

[32]  J. Baselga,et al.  Phase I study of the humanized antiepidermal growth factor receptor monoclonal antibody EMD72000 in patients with advanced solid tumors that express the epidermal growth factor receptor. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[33]  J. Su,et al.  Expression of focal adhesion kinase and alpha5 and beta1 integrins in carcinomas and its clinical significance. , 2002, World journal of gastroenterology.

[34]  R. Theriault,et al.  Increased levels of alpha6 integrins are associated with the metastatic phenotype of human breast cancer cells. , 1999, Clinical & experimental metastasis.