Metastatic breast cancer cells in the bone marrow microenvironment: novel insights into oncoprotection

Abstract

Among all cancers, malignancies of the breast are the second leading cause of cancer death in the United States after carcinoma of the lung. One of the major factors considered when assessing the prognosis of breast cancer patients is whether the tumor has metastasized to distant organs. Although the exact phenotype of the malignant cells responsible for metastasis and dormancy is still unknown, growing evidence has revealed that they may have stem cell-like properties that may account for resistance to chemotherapy and radiation. One process that has been attributed to primary tumor metastasis is the epithelial-to-mesenchymal transition. In this review, we specifically discuss breast cancer dissemination to the bone marrow and factors that ultimately serve to shelter and promote tumor growth, including the complex relationship between mesenchymal stem cells (MSCs) and various aspects of the immune system, carcinoma-associated fibroblasts, and the diverse components of the tumor microenvironment. A better understanding of the journey from the primary tumor site to the bone marrow and subsequently the oncoprotective role of MSCs and other factors within that microenvironment can potentially lead to development of novel therapeutic targets.

Fig. 1

Polarized epithelial cells at the primary tumor site may acquire mesenchymal-like properties enabling these cells to transverse the basement membrane and enter the vasculature [14, 15, 17]. Once these cells migrate to distant metastatic sites and pass into the interstitial space, mesenchymal-to-epithelial reversion may occur, facilitating establishment of these malignant cells permanently in the secondary site where they can establish dormancy [14, 15, 17]

Fig. 2

Mesenchymal stem cells within the bone marrow stroma exert an oncoprotective role on migrant breast cancer cells through complex interactions with components of the immune system. It is possible that a small subpopulation of breast cancer cells responsible for metastasis harbors stem-like qualities, and this subpopulation may serve as a target for therapy [–32]. T_regs regulatory T cells, NK natural killer cells, CTL cytotoxic T lymphocytes

Fig. 3

The generation of carcinoma-associated fibroblasts from mesenchymal stem cells provides a protective and trophic environment for breast cancer progression. Autocrine signaling loops involving TGF-β and SDF-1 promote immune suppression and chemotaxis, respectively, which have important implications in breast cancer dormancy in metastatic sites. The targeting of these signaling loops may serve as an avenue through which breast cancer remission or treatment can be achieved

Fig. 4

Current chemotherapeutic and radiation therapies target the rapidly dividing cells which make up the bulk of the tumor, but may leave behind the slower cycling stem-like cells. These cells are expected to self-renew and give rise to new tumors limitlessly [48, 49]. The pluripotency marker Oct-4 is shown here as a potential marker of these cancer-initiating cells

Fig. 5

a Resident stem cells of a given tissue have the ability to undergo asymmetric division in which the stem cell self-renews and gives rise to a committed progenitor. Upon loss of genomic stability, resident stem cells may become transformed. b Stem-like breast cancer cells, which undergo self-renewal and multi-lineage differentiation, may have similar properties to pluripotent stem cells and can give rise to serial tumorspheres [54, 55]. They are thought to establish gap junctions with bone marrow stroma and adopt a quiescent phenotype, serving as a source of tertiary metastasis