signature=a9f9b98a534a681cdb853239de55020c,Evaluation of the tumor microenvironment for metastasis (...

Abstract

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Multiphoton-based intravital imaging (IVI) has demonstrated that carcinoma cells of living mouse metastatic PyMT mammary tumors exhibit chemotaxis toward blood vessels. A paracrine loop involving tumor cells secreting CSF-1 and macrophages secreting EGF results in the convergence of macrophages and tumor cells around blood vessels. The paracrine loop creates a microenvironment that leads to the expression of genes that enhance EGF-dependent chemotaxis and metastasis. This tumor microenvironment for metastasis (TMEM) and its associated expression profile, the invasion signature, has been defined in the mouse PyMT mammary tumor model (Condeelis et al. 2005 Ann. Rev. CDB 21:695). Mena is a key master gene in the invasion signature and is a marker for invasive tumor cells. The purpose of this study was to expand on earlier findings in which IVI observations in PyMT tumors were correlated with human breast cancer samples. Triple stain immunohistochemistry for vessels, macrophages, and mena expression was performed and analyzed in four compartments: invasive carcinoma, in situ carcinoma (DCIS), non-neoplastic breast parenchyma in samples containing tumor elsewhere, and breast tissue from reduction mammoplasty specimens. Absolute numbers of macrophages and blood vessels were determined for each compartment as well as the absence or presence and extent of the tumor microenvironment for metastasis (TMEM). TMEM is defined as the presence of a tripartite arrangement of a macrophage and a mena-expressing tumor cell no more than 1 cell diameter from each other and from a blood vessel. The numbers of blood vessels and macrophages are increased in breast tissue containing carcinoma. The highest density of macrophages in DCIS is at the epithelial-stromal interface. The highest macrophage and blood vessel densities overall are in the invasive carcinoma. Mena expression is seen in DCIS, invasive carcinoma (consistent with a previous study - see DiModugno et al 2006 Clin Cancer Res. 12:1470) and glands from reduction mammoplasties, but not in the non-neoplastic glands adjacent to the carcinomas. The distribution of mena is variably peripheral or localized to cell protrusions, similar to what has been observed in IVI of the PyMT tumors. TMEM is seen only invasive carcinoma. The findings suggest that, as in animal models, TMEM is important to intravasation and metastasis in human breast cancer and may be a prognostic marker in humans.