Breast cancer by proxy: can the microenvironment be both the cause and consequence?

Abstract

Breast cancer is one of the most clear-cut examples of a solid tumor in which systemic cues play a decisive part in its development. The breast tissue is constantly subjected to changes in hormone levels and modifications in the microenvironment. This scenario is even more striking during tumor development because of the dramatic loss or aberration of basement membrane (BM) and myoepithelial cells and the gain of peritumoral myofibroblasts. We suggest that the microenvironment, defined here as all components of the mammary gland other than luminal and/or tumor epithelial cells, might be instrumental in maintaining organ integrity and in promoting, and at times even initiating, breast cancer development. As such, the tumor microenvironment and its constituents, alone or in combination, might serve as promising targets for therapy.

Figure 1

Breast cancer development is an intricate and involved process implicating reciprocal interactions between epithelial cells, the stromal cells and the ECM. (a) Normal breast is characterized by a high level of architectural integrity. Polarized, luminal epithelium is surrounded by myoepithelium, and the entire epithelium is separated from the surrounding interstitial stroma by an intact BM. The stroma comprises vasculature, fibroblasts and macrophages embedded in BM and ECM characteristic of normal breast. (b) The classical perception of initiation of tumor development is that cancer originates from mutagenic or epigenetic insults to a single cell in the epithelium (lightning). Recent studies suggest that LOH or epigenetic events in stromal cells might promote or even initiate genetic instability and tumor development. Likewise, changes in ECM composition, genetic defects in specific ECM molecules or global changes, such as those occurring due to aging, might be implicated. (c) Promotion of tumor development relies on the proliferation of mutated epithelial cells (double bar depicts mitosis) and the alteration and/or loss of myoepithelial cells and BM. Resident fibroblasts are converted into myofibroblasts, and other stromal cells, such as resident vascular smooth muscle (vsm) cells, blood-borne fibrocytes and/or bone-marrow-derived mesenchymal cells, might be recruited from the vasculature to participate in direct epithelial—stromal interactions. Hypoxia leads to macrophage infiltration and angiogenesis. From this point on, the ECM is subjected to major structural and functional changes. (d) Progression to invasive breast carcinoma is characterized by a complete loss or alteration of myoepithelial cells and BM, and the highly aberrant tumor cells are now surrounded by a fully activated stroma, often characterized by desmoplasia that allows and indeed encourages invasion. Tumor cells also might invade vessels to establish metastases in other organs (not depicted).

Figure 2

Vascular smooth muscle cells recruited from venous blood vessels might contribute to reactive stroma. Using triple-staining of cryosections of human breast tumors, we demonstrated that (a) in tumors with no or few smooth-muscle-differentiated myofibroblasts, blood vessels (bv) are intact, whereas (b) in tumors with foci of distinct smooth-muscle-differentiated myofibroblasts, blood vessels within the same area are dramatically stripped of vascular smooth muscle cells. Tumor cells (t) were recognized by cytokeratin 18 (blue), and endothelial cells and vascular smooth muscle cells (vsm) of blood vessels were labeled by endothelial surface antigen (red) and smooth-muscle-myosin heavy chain (green), respectively. We suggest that such differences in myofibroblast differentation could be used to classify patients in terms of the kind of treatment needed. Reproduced from Ref. [11] with permission from the American Society for Clinical Investigation. Magnification: (a) x400; (b) x640.