The Integrin-Extracellular Matrix Axis in Pancreatic Cancer

Abstract

Pancreatic cancer is the fifth leading cause of adult cancer death in the United States, with 5-year survival rates of only 1% to 4%. Current therapeutic strategies generally result in only a few months of extended life. Recent evidence from several independent laboratories in vitro and in vivo indicate that integrin-mediated cell attachment to the extracellular matrix (ECM), components of which are highly up-regulated in pancreatic cancer, evokes phenotypes and signaling pathways that regulate tumor cell growth and migration. In this review, we will discuss our current understanding of the role of the ECM in directing pancreatic cancer growth, progression, and metastasis. Topics covered include a survey of the existing literature regarding the in vivo and in vitro expression of the ECM and its cell surface receptors, the integrins, in pancreatic cancer; mechanisms involved in the integrin-ECM-mediated malignant phenotype; and future directions for the study of the integrin-ECM axis and its role in pancreatic cancer progression, including potential therapeutic strategies.

Dynamic contrast-enhanced MRI of the microenvironment of pancreatic adenocarcinoma xenografts

“…The tumors develop a dense collagen-rich extracellular matrix [26], consistent with the observation that collagen I is up-regulated in human PDAC [34]. In BxPC-3 and Capan-2 tumors, the collagen fibers appear in thick filament bundles, whereas in MIAPaCa-2 and Panc-1 tumors, the collagen is seen as a dense network of thin fibers surrounding single tumor cells [26].…”

Activation of the α2β1 integrin‐mediated malignant phenotype on type I collagen in pancreatic cancer cells by shifts in the concentrations of extracellular Mg2+ and Ca2+

“…43,44 only the expression of the a 1 b 1 and a 2 b 1 integrins has been examined in pancreatic adenocarcinoma so far. 25 Results from these previous studies indicate that both the a 1 b 1 and a 2 b 1 integrins are expressed in vivo at both the mRNA and protein levels in pancreatic cancer. In vitro, a 2 b 1 integrin expression has been shown in 18/19 cell lines (95%), while a 1 b 1 integrin expression has been demonstrated in 7/13 cell lines (54%).…”

“…3,4,[6][7][8][9][10][11] These cations presumably exert their effects by binding to the 3-5 putative cation-binding domains located on all integrin a subunits, 12 and possibly by interacting directly with b subunits. 13 We have recently demonstrated that a 2 b 1 integrin-mediated pancreatic cancer cell adhesion to Type I collagen, an ECM protein shown to be highly upregulated in pancreatic cancer [14][15][16][17] and to promote the malignant phenotype in vitro and in vivo, [18][19][20][21][22][23][24][25] is promoted in 1.5 mM Mg 21 and inhibited in 1.5 mM Ca 21 , 21 and that the a 2 b 1 integrin from pancreatic cancer cell lysates bound specifically to Type I collagen by affinity chromatography in 3 mM Mg 21 , can be eluted with 3 mM Ca. 2126 These data are consistent with our previous observations regarding the a 2 b 1 integrin, Type I collagen, and the various cell types involved in cutaneous wound repair, [27][28][29] of which strong parallels to the pancreatic cancer paradigm have been described.…”

Targeting stromal microenvironment in pancreatic ductal adenocarcinoma: controversies and promises

“…Secreted by CAFs, these stromal elements not only provide structural support but are also involved in differentiation, remodeling and carcinogenesis. Collagen I was shown to promote gemcitabine resistance in vitro (22,23). It also interacted with collagen IV and integrins on the surface of PDA cancer cells, and is vital for proliferation, maintenance of migratory phenotype, and avoiding apoptosis (24).…”