Peripheral lymph node stromal cells can promote growth and tumorigenicity of breast carcinoma cells through the release of IGF-I and EGF

Abstract

The regional lymph nodes draining primary breast carcinomas are generally the first site to be invaded by disseminating tumor cells. The extent of lymph node involvement remains the most reliable indicator for staging and prognosis of breast cancer. We have investigated host-tumor interactions between breast carcinoma cells and the lymph node stroma, which may control the outcome of lymph node infiltration. In a previous study, we identified integrin-mediated cell adhesion as a correlate of the metastatic potential of human and rat carcinoma cells. Our present objective was to determine whether lymphatic stromal cells can affect cancer cell growth through the elaboration of growth-modulating factors. Two lymphatic stromal cell lines, ST-A4 and ST-B12, were established from normal rat lymph node stromal cell cultures. SFM conditioned by these cells increased the proliferation of human (Hs578T and MCF-7) and rat (TMT-081) breast carcinoma cells by up to 7-fold and augmented their ability to form colonies in semisolid agar by up to 41-fold. This effect was specific as normal, diploid human breast epithelial cells (Hs578Bst), a nontumorigenic, immortalized human breast epithelial cell line (MCF-10A) and a nonmetastatic rat mammary carcinoma cell line (MT-W9B) had either no or reduced responses. RT-PCR analysis revealed that both lymph node stromal cell lines expressed mRNA transcripts for multiple growth factors, including IGF-I, EGF, HGF and PDGF-alpha, and produced detectable levels of IGF-I, EGF and PDGF-alpha, as assessed by Western blotting. Antibody-mediated depletion assays identified IGF-I and EGF as the major mitogenic factors in the CM. The identification of these cells raises the possibility that the lymph node microenvironment may contribute actively to the process of cancer cell dissemination.