Mary M. Zutter, M.D.
Molecular basis of cell adhesion to collagen with a focus on the alpha2 beta1 integrin
Cancer progression involves fundamental alterations of cell-cell and cell-matrix interactions and the cues derived from them that contribute to the invasive and metastatic phenotype. As important mediators of cell adhesive behavior, integrins play a critical role in tumor progression and metastasis. Their role in mediating adhesion to either components of the extracellular matrix or to other cells is now well established.
Our laboratory focuses on the molecular basis of cell adhesion to collagen with a focus on the alpha2 beta1 integrin. The alpha2 beta1 integrin, a receptor for collagens, laminins, decorin, E-cadherin, as well as other ligands, has been implicated in normal developmental, inflammatory, and oncogenic processes. We use cell and molecular biology, mouse models of cancer, and organotypic model systems to address questions in cancer biology, immunology, and hemostasis.
1. The alpha2 beta1 integrin: a regulator of breast cancer metastasis.
The alpha2 beta1 integrin is expressed at high levels by most normal epithelial cells. In many epithelial malignancies alpha2 beta1 integrin expression is diminished or lost in a manner that correlates with the loss of epithelial differentiation and tumor progression. To characterize the role of the alpha2 beta1 integrin in tumor biology we utilized genetically engineered mice (GEM) in which expression of the Î±2Î²1 integrin is completely eliminated. Early studies provided the initial correlative suggestion that loss of alpha2 beta1 integrin expression might play an important role in cancer progression. Alternatively, loss of alpha2 beta1 integrin expression may simply be a consequence of malignant progression. In other studies, however, using cell lines either in vivo or in vitro suggest that the alpha2 beta1 integrin may serve to enhance metastasis to different organs.
The results of in vitro and in vivo studies of various designs may be subject to conflicting interpretation. Therefore, we have explored the role of the alpha2 beta1 integrin in cancer initiation and progression using a clinically-relevant, spontaneous mouse model, the MMTV-Neu model of breast cancer progression and metastasis. Furthermore, we have validated and extended the conclusions of our model system with a detailed analysis of Î±2 integrin gene expression and its significance in human breast and prostate cancer. We demonstrate that the alpha2 beta1 integrin is a metastasis suppressor of breast cancer and we identify key mechanistic steps in the metastatic cascade enhanced by loss of alpha2 beta1 integrin expression.
Although, the contribution of alpha2 beta1 integrin expression to metastasis suppression is clear, these data raise important questions which are the focus of ongoing work in the laboratory to dissect the molecular mechanisms by which alpha2 beta1 integrin suppresses the metastatic phenotype. Studies are ongoing to define the role of the integrin expression or lack thereof on the tumor cells alone, on cells within the host microenvironment alone, or the contribution on both the tumor cells and within the host microenvironment in tumor metastasis.
2. The alpha2 beta1 integrin and the innate immune response.
The alpha2 beta1 integrin is expressed on activated T lymphocytes, natural killer cells, other inflammatory cells, and mast cells. We have recently discovered that the alpha2 beta1 integrin is a novel receptor for multiple collectins and the C1q complement protein and is required for the innate immune response. The alpha2 beta1 integrin provides a co-stimulatory signal required for mast cell activation, cytokine secretion and initiation of innate immunity. We recently demonstrated that crosstalk between c-met/hepatocyte growth factor receptor and the alpha2 beta1 integrin contributes to mast-cell activation. Ongoing projects are directed toward understanding the role that the alpha2 beta1 integrin plays in immune modulation in the tumor microenvironment.