Principal Investigator Robert Weinberg
Previous work indicated that the transformation of human cells is a complex, multi-step process that requires the deregulation of at least five distinct signaling pathways operating in these cells – those involving telomerase and telomere maintenance, the pRb (retinoblastoma protein) pathway, the p53 tumor suppressor pathway, the Ras mitogenic signaling pathway, and a poorly understood pathway that is governed by PP2A (protein phosphatase 2A). We have found that the deregulation of this pathway in a wide spectrum of normal human cells enables their transformation into tumorigenic cells. We have recently developed a method by which we can insert human mammary fibroblasts into a mouse mammary fat pad; subsequent implantation of normal human mammary epithelial cells into the humanized stroma results in normal human mammary gland morphogenesis and occasionally in the development of growths that are indistinguishable from ductal hyperplasias, in situ carcinomas, and invasive carcinomas. Together, this experimental system enables us to model all of the steps of human mammary gland morphogenesis and, it seems, carcinoma pathogenesis. Development of a method for culturing mammary epithelial stem cells affords us the means of generating genetically defined human breast carcinoma cells that generate growths virtually indistinguishable from those seen in patients in the clinic. Importantly, we have demonstrated that when human mammary epithelial cells are transformed into tumor cells, these cells must recruit stromal cells (e.g., fibroblasts, endothelial cells, macrophages) into their midst before they form carcinomas.
Research has revealed that several mesenchymal cell types that form the tumor-associated stroma are important in supporting carcinoma cell growth within the tumor. Thus, mesenchymal stem cells and myofibroblasts in the tumor-associated stroma can release paracrine signals that impart invasive and metastatic powers to nearby carcinoma cells. At the same time, primary carcinomas release endocrinal signals that impinge on the bone marrow and spleen and induce the formation of several types of inflammatory cells that may then be recruited by tumors , via the general hematogenous circulation, to help the tumors to rapidly assemble a highly functional, tumor-supporting stroma. We are currently investigating the mechanism(s) by which this recruitment occurs. In addition, we have determined that the stromal fibroblasts that are present in human mammary carcinomas are biologically abnormal and are in an activated state reminiscent of that of myofibroblasts. Together, these interactions indicate that cancer is a systemic disease long before systemic dissemination of cancer cells has begun.