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Tumor Stoma and the Growth of Carcinomas. Carcinomas arise in epithelial tissues that are composed of both epithelial and stromal cells. The latter encompass a variety of mesenchymal cell types, including fibroblasts, myofibroblasts, adipocytes, macrophages, mast cells, endothelial cells, pericytes, and lymphocytes. Normal epithelial cells depend on various types of cell physiologic support in order to sustain their survival and proliferation. While the process of tumor progression yields cells that acquire increasing independence from stromal support, the great majority of carcinomas are formed from neoplastic cells that continue to be dependent on nearby stroma.
We have been interested in the possibility that the stroma of a tumor changes as tumor progression advances. Thus, we have undertaken a series of experiments in which weakly growing carcinoma cells are mixed with the stromal cells extracted from a number of human breast carcinomas. The growth the resulting mixed tumors has then been followed and has revealed that the stromal cells from the majority of breast cancers are more competent to drive tumor progression than are the stromal cells from the normal human breast. This change in biological make-up is reflected by the change in the types of fibroblasts that are present in the tumor-associated stroma: myofibroblasts increasingly replace fibroblasts. Tumors arising through the admixture of myofibroblasts show a greatly increased vascularization, indicating that angiogenesis is a key factor in limiting tumor growth, and that the latter can be accelerated by providing myofibroblasts with potent angiogenesis-inducing powers.
The mechanism(s) used by myofibroblasts to accelerate angiogenesis are quite interesting. These cells release a cytokine, call variously stroma-derived factor-1 (SDF-1) or CXCL12. The latter encourages the recruitment of endothelial precursor cells (EPCs) from the circulation into the tumor-associated stroma, whereupon the EPCs are induced to differentiate into the endothelial cells that proceed to construct the capillaries forming the tumor-associated neovasculature. Because angiogenesis is a rate-limiting step in tumor formation, the presence of these myofibroblasts in the tumor-associated stroma greatly accelerates the growth of the tumor as a whole.
A topic of great interest is the origins of the tumor-associated stromal cells. While many may originate through proliferation of stromal cells in the normal, adjacent host stroma, others may originate in the circulation and thus in the bone marrow of the host. Indeed, we have found that primary tumors are able to encourage the mobilization and recruitment of stromal fibroblasts from the bone marrow, indicating that such tumors extend their reach to distant corners of the body in order to expedite their own agenda of proliferation. Our current research is focused on identifying the nature of the signals released by primary tumors in order to stimulate this stromal recruitment and on the identities of the bone marrow cell populations that serve as precursors to tumor-associated stromal cells.
