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.

A Novel Model of Dormancy for Bone Metastatic Breast Cancer Cells

“…However, the mechanisms underlying metastatic cell dormancy and relapse from dormancy remains one of the most challenging, but also most clinically relevant questions (3,8,13). Approximately one third of patients with breast cancer have detectable DTCs in bone marrow in early stages of disease (1).…”

“…In breast cancer, particularly in the estrogen receptor (ER)-positive subtype, the most frequent site of metastasis is the bone (5,6). It has also been proposed that bone marrow is the origin of secondary cancer-cell dissemination to viscera, even when bone macrometastases are not detectable (8,9). These clinical characteristics indicate that targeting the early steps of extravasation and dissemination may not be as efficacious as targeting DTC (3,4).…”

Antiproliferative Effects of Local Anesthetics on Mesenchymal Stem Cells

“…27,28 Although some controversies exist with respect to the definite role of MSC in tumor growth and propagation, most recent in vivo studies clearly demonstrate their high potential to boost tumor growth and metastasis by the release of growth factors, enhanced angiogenesis, immunomodulation, and a phenomenon called "epithelialto-mesenchymal transition," a process whereby MSC transform into "carcinoma-associated fibroblasts" and promote the dedifferentiation and spreading of tumor cells into the body. 29 On the other hand, MSC are essential elements in tissue repair 30 and thus are currently used in numerous investigational regenerative therapies for otherwise incurable diseases. 31 Our experiments show the following salient findings.…”

Inhibition of ZNF746 suppresses invasion and epithelial to mesenchymal transition in H460 non-small cell lung cancer cells

“…There is accumulating evidence that EMT plays an important role in cancer progression, wound healing, invasion and tissue fibrosis as well as in embryogenesis (4)(5)(6). The EMT process results in the loss of epithelial cell phenotype and exhibits mesenchymal cell characteristics.…”