α2β1 integrin expression in the tumor microenvironment enhances tumor angiogenesis in a tumor cell–specific manner

Abstract

To define the role of the ␣2␤1 integrin in pathologic angiogenesis, we investigated tumor-associated growth and angiogenesis in wild-type and ␣2-null mice. Our findings reveal that the ␣2␤1 integrin plays an important role in angiogenesis via regulation of VEGFR1 expression. When challenged with B16F10 melanoma cells, mice lacking ␣2␤1 integrin expression exhibit increased tumor angiogenesis associated with up-regulated VEGFR1 expression. In contrast, there was no ␣2␤1 integrin-dependent difference in the angiogenic response to Lewis lung carcinoma (LLC) cells. Interestingly, whereas B16F10 cells secrete high levels of placental growth factor (PLGF), LLC cells produce high levels of VEGF, but low levels of PLGF. The ␣2␤1 integrindependent difference in angiogenesis was restored to LLC cells by expression of PLGF, strongly suggesting that the angiogenic phenotype and tumor growth in the ␣2-null host is dependent on specific interactions between the tumor cell and the genetically defined integrin repertoire of the host microenvironment. Thus integrin ␣2-null mice represent an example of genetic alterations of "the soil" determining response to the "seed." (Blood. 2008; 111:1980-1988 © 2008 by The American Society of Hematology IntroductionTumor initiation and progression involve complex interactions between tumor cells and their microenvironment. 1 Integrins are expressed on both tumor cells and cells of the microenvironment where they modulate tumor initiation, progression, and angiogenesis. [2][3][4][5] Several integrins, including the ␣v␤3, ␣v␤5, ␣4␤1, and ␣5␤1 have been implicated in angiogenesis. [6][7][8][9] The ␣1␤1 and ␣2␤1 integrins, the 2 major collagen receptors, have also been implicated in the pathobiology of tumor angiogenesis. [10][11][12][13][14][15][16][17] Genetic deletion of the ␣1␤1 integrin supported the concept that the ␣1␤1 integrin was proangiogenic. 16,17 The ␣1-deficient mice demonstrate decreased tumor growth and angiogenesis, a finding consistent with the ␣1␤1 integrin serving a proangiogenic function. Recent wound healing studies in wild-type and ␣2␤1 integrin-deficient mice demonstrated that deletion of the ␣2␤1 integrin resulted in increased neoangiogenesis, suggesting that the ␣2␤1 integrin plays a negative role in regulating neoangiogenesis within the wounded microenvironment. 18,19 In this present study we investigated the molecular mechanisms whereby loss of the ␣2␤1 integrin leads to increased neovascularization, particularly in the context of tumor-associated angiogenesis. We show that the ␣2␤1 integrin plays an unexpected role in regulating tumor neoangiogenesis in vivo. Expression of the ␣2␤1 integrin is up-regulated on endothelium within the tumor microenvironment. Unlike ␣1-null mice, ␣2-null mice exhibit increased tumor angiogenesis and consequent increased tumor growth when challenged with B16F10 melanoma cells. Increased expression of vascular endothelial cell growth factor receptor 1 (VEGFR-1) on ␣2-null endothelial cells within the tumor microenvironment is in part re...

Endothelial α3β1-Integrin Represses Pathological Angiogenesis and Sustains Endothelial-VEGF

“…In contrast to previous studies on the effect of the global genetic ablation of ␣v␤3 or ␣2␤1 on angiogenesis, 29,30,[45][46][47] which includes the effects of the deletion of these integrins in many cell types on neovascularization, our study is the first to dissect the precise role of ␣3␤1 integrin in endothelial cells in vivo. It is noteworthy that although ␣v␤3-integrin deficiency also enhances angiogenic responses by elevating Flk-1 levels, 29,30,45 and that endothelial ␣6 integrin deficiency is associated with increased Flk-1 levels, 48 the regulation of Flk-1 is at the transcriptional level in the ␣3-null endothelial cells but at the protein level in ␤3-null and ␣6-null endothelial cells.…”

α2β1 integrin controls association of Rac with the membrane and triggers quiescence of endothelial cells

“…Mice lacking 21 integrin present increased production of MMPs upon wounding, which might contribute to remodeling of the extracellular matrix and stimulation of angiogenesis (Grenache et al, 2007). The increased tumor angiogenesis has been linked to a compensatory mechanism involving VEGFR1 overexpression in endothelial cells in which 2 integrin is knocked out (Zhang et al, 2008). Nevertheless, a relief of dominance exerted by 2 integrin on other integrins might also cause increased angiogenesis.…”

The α2β1 integrin is a metastasis suppressor in mouse models and human cancer

“…Intravasation assays were carried out with WT primary pulmonary endothelial cells, prepared as previously described (55). Endothelial cells (5 × 10 4 ) were seeded on the bottom side of a Transwell filter, precoated with growth factor-reduced Matrigel (1:20), and cultured in growth medium overnight.…”