Journal
BIOCHIMICA ET BIOPHYSICA ACTA-REVIEWS ON CANCER
Volume 1869, Issue 2, Pages 321-332Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbcan.2018.04.005
Keywords
Cadherin 17; VE-cadherin; CDH6; alpha 2 beta 1 integrin; RGD motif; Type IV collagen; Metastasis; Therapeutic antibodies
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Funding
- MINECO [BIO2015-66489-R]
- Ramon Areces Foundation [CIVP18 A3884]
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We propose a new cadherin family classification comprising epithelial cadherins (cadherin 17 [CDH17], cadherin 16, VE-cadherin, cadherin 6 and cadherin 20) containing RGD motifs within their sequences. Expression of some RGD cadherins is associated with aggressive forms of cancer during the late stages of metastasis, and CDH17 and VE-cadherin have emerged as critical actors in cancer metastasis. After binding to alpha 2 beta 1 integrin, these cadherins promote integrin beta 1 activation, and thereby cell adhesion, invasion and proliferation, in liver and lung metastasis. Activation of alpha 2 beta 1 integrin provokes an affinity increase for type IV collagen, a major component of the basement membrane and a critical partner for cell anchoring in liver and other metastatic organs. Activation of alpha 2 beta 1 integrin by RGD motifs breaks an old paradigm of integrin classification and supports an important role of this integrin in cancer metastasis. Recently, synthetic peptides containing the RGD motif of CDH17 elicited highly specific and selective antibodies that block the ability of CDH17 RGD to activate alpha 2 beta 1 integrin. These monoclonal antibodies inhibit metastatic colonization in orthotopic mouse models of liver and lung metastasis for colorectal cancer and melanoma, respectively. Hopefully, blocking the cadherin RGD ligand capacity will give us control over the integrin activity in solid tumors metastasis, paving the way for development of new agents of cancer treatment.
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