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Integrins regulate cell-cell and cell-matrix adhesion and thereby play critical roles in tumor progression and metastasis. Although work in preclinical models suggests that β 1 integrins may stimulate metastasis of a number of cancers, expression of the β 1 subunit alone has not been shown to be a useful prognostic indicator in human cancer patients. Here we have demonstrated that the α 2 β 1 integrin suppresses metastasis in a clinically relevant spontaneous mouse model of breast cancer. These data are consistent with previous studies indicating high expression of α 2 β 1 integrin in normal breast epithelium and loss of α 2 β 1 in poorly differentiated breast cancer. They are also consistent with our systematic analysis of microarray databases of human breast and prostate cancer, which revealed that decreased expression of the gene encoding α 2 integrin, but not genes encoding α 1 , α 3 , or β 1 integrin, was predictive of metastatic dissemination and decreased survival. The predictive value of α 2 expression persisted within both good-risk and poor-risk cohorts defined by estrogen receptor and lymph node status. Thus, the α 2 β 1 integrin functionally inhibits breast tumor metastasis, and α 2 expression may serve as an important biomarker of metastatic potential and patient survival.

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...

To compare the pathogenesis of human genotype 1 (HuG1) and bovine genotype 2 (BoG2) Cryptosporidium parvum, neonatal gnotobiotic pigs were given 1-10 HuG1 or BoG2 oocysts. The prepatent and patent periods were significantly longer for HuG1 than for BoG2 C. parvum (prepatent, 8.6 vs. 5.6 days; patent, 16.6 vs. 10.3 days). BoG2-infected pigs developed significantly more severe disease than did HuG1-infected pigs. BoG2 parasites were seen microscopically throughout the intestines during the prepatent and patent periods. HuG1 parasites were only detected during the patent period in the ileum and colon but colonized the mucosal surface in significantly larger numbers than did BoG2. Moderate-to-severe villus/mucosal attenuation with lymphoid hyperplasia was seen throughout the intestines of BoG2-infected pigs, whereas lesions in HuG1-infected pigs were mild to moderate and restricted to the ileum and colon. These findings provide additional support for the hypothesis that human and bovine C. parvum genotypes may be separate species.

No abstract

Most waterborne outbreaks of cryptosporidiosis have been attributed to agricultural sources due to the high prevalence of Cryptosporidium oocysts in animal wastes and manure spreading on farmlands. No-till, an effective conservation practice, often results in soil having higher water infiltration and percolation rates than conventional tillage. We treated six undisturbed no-till and six tilled soil blocks (30 by 30 by 30 cm) with 1 L liquid dairy manure containing 10(5) C. parvum oocysts per milliliter to test the effect of tillage and rainfall on oocyst transport. The blocks were subjected to rainfall treatments consisting of 5 mm or 30 mm in 30 min. Leachate was collected from the base of the blocks in 35-mL increments using a 64-cell grid lysimeter. Even before any rain was applied, approximately 300 mL of water from the liquid manure (30% of that applied) was transported through the no-till soil, but none through the tilled blocks. After rain was applied, a greater number and percentage of first leachate samples from the no-till soil blocks compared to the tilled blocks tested positive for Cryptosporidium oocysts. In contrast to leachate, greater numbers of oocysts were recovered from the tilled soil, itself, than from the no-till soil. Although tillage was the most important factor affecting oocyst transport, rainfall timing and intensity were also important. To minimize transport of Cryptosporidium in no-till fields, manure should be applied at least 48 h before heavy rainfall is anticipated or methods of disrupting the direct linkage of surface soil to drains, via macropores, need to be used.

The α2β1 integrin is a receptor for collagens, laminins and other adhesive molecules. Our early observations regarding the expression of the α2β1 integrin in tissues revealed that expression of the integrin is associated with orderly regulated epithelial proliferation. Our subsequent observation that the diminution or loss of α2β1 integrin expression in epithelial tumors correlated with loss of epithelial differentiation during cancer progression was consistent with this postulate and has spawned much work on the role of epithelial α2β1 integrin. However, the α2β1 integrin is expressed not only on tumor epithelial cells, but also on endothelial cells, fibroblasts and hematopoietic cells within the tumor microenvironment, necessitating an examination of the role of the α2β1 integrin in the tumor microenvironment. The role of the integrin in angiogenesis had been previously evaluated using inhibitory antibodies by Senger and colleagues who argued that collagen receptors within the microenvironment of tumors were critical for the development of new vessels. Our laboratory has now used the α2β1 integrin‐deficient mouse to explore the role of the integrin in the tumor microenvironment. Our recent data indicate that the α2β1 integrin plays an important role in regulating not tumor initiation, but tumor progression.