Bone Marrow-Derived Cells in Endometrial Cancer Pathogenesis: Insights from Breast Cancer

Abstract

Endometrial cancer is the most common gynecological cancer, representing 3.5% of all new cancer cases in the United States. Abnormal stem cell-like cells, referred to as cancer stem cells (CSCs), reside in the endometrium and possess the capacity to self-renew and differentiate into cancer progenitors, leading to tumor progression. Herein we review the role of the endometrial microenvironment and sex hormone signaling in sustaining EC progenitors and potentially promoting dormancy, a cellular state characterized by cell cycle quiescence and resistance to conventional treatments. We offer perspective on mechanisms by which bone marrow-derived cells (BMDCs) within the endometrial microenvironment could promote endometrial CSC (eCSC) survival and/or dormancy. Our perspective relies on the well-established example of another sex hormone-driven cancer, breast cancer, in which the BM microenvironment plays a crucial role in acquisition of CSC phenotype and dormancy. Our previous studies demonstrate that BMDCs migrate to the endometrium and express sex hormone (estrogen and progesterone) receptors. Whether the BM is a source of eCSCs is unknown; alternatively, crosstalk between BMDCs and CSCs within the endometrial microenvironment could be an additional mechanism supporting eCSCs and tumorigenesis. Elucidating these mechanisms will provide avenues to develop novel therapeutic interventions for EC.

Keywords: bone marrow niche; breast cancer; cancer stem cells; dormancy; endometrial cancer; endometrium.

Figure 1

Proposed mechanisms by which BMDCs promote endometrial cancer cell (ECC) dormancy: Insights from breast cancer (A) (1) Breast cancer cells (BCCs) metastasize to the bone marrow (BM) and undergo dormancy acquisition facilitated by secretome exchange with perivascular mesenchymal stem cells (MSCs). (2) Dormant BCCs exhibit properties of cancer stem cells (CSCs) and establish residence at the endosteal niche where they interact with stromal cells via gap junction intercellular communication (GJIC), resulting in dormancy maintenance. (B) (1) BMDCs, including BM-MSCs, are recruited to the endometrium to potentially initiate ECC dormancy. (2) Mechanistically, we propose that BM-MSCs may support EC dormancy in two ways. First, (a) BM-MSCs release exosomes containing miRNAs that may initiate dormancy and (3) de-differentiation of ECCs by regulating Wnt/Notch signaling. Another mechanism may be via (b) BM-MSC differentiation into eMSC which, in turn, release exosomes that facilitate ECC dormancy and (3) de-differentiation into CSCs. Ultimately, de-differentiation of ECCs into CSCs results in resistance to treatment and immune evasion, allowing the tumor to persist for extended periods.