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  • XL 184 br Erythropoietin and the HSC niche Many molecules pr

    2019-05-05


    Erythropoietin and the HSC niche Many molecules produced both locally and systemically, including erythropoietin (Epo) and adrenergic catecholamines, also appear to affect HSC niche and metastatic lesions in the bone marrow. EPO is a hematopoietic hormone produced predominantly in the kidneys in response to hypoxia. EPO functions through binding to a preformed homodimer transmembrane receptor (Epo-R). Interestingly, Epo-R is expressed in both hematopoietic and non-hematopoietic tissues, suggesting that the role of Epo may be more widespread beyond hematopoiesis [25]. The mRNA expression of Epo-R has been reported in tissues of the brain, testes, placenta, heart, lungs, bone marrow, spleen, and even tumor XL 184 [26–28]. In cancer, Epo has both direct and indirect actions on DTCs in the HSC niche. First, Epo may directly act on tumor cells located within the bone marrow. Some studies provide evidence that Epo/Epo-R axis activation leads to tumor cell proliferation; while other studies demonstrate Epo/Epo-R activation did not support tumor cell growth specifically [29]. Interestingly, Shiozawa et al. [30] demonstrated that Epo did not stimulate PCa tumor cell (using PCa cell lines) proliferation in vitro, or enhance metastasis in vivo; however, these authors did demonstrate an increased tumor cell resistance to apoptosis resulting in PCa cell survival. Similarly, Todaro et al. [31] reported that Epo stimulation increased resistance of breast cancer stem-like cells (BCSC) isolated from patient tumors to chemotherapeutics, doxorubicin and 5-FU, in vitro and in a subcutaneous mouse model. Further, they reported stimulation with Epo upregulated known survival pathway mediators—Akt, Erk, and Bcl-xL—which may explain the mechanism by which BCSC cells achieved protection from chemotherapy [31]. These remain among the possible mechanisms that affect cancer therapy and may impact patient survival, through resistance of DTCs within the bone marrow to current chemotherapeutics [32]. There is also evidence that Epo increases niche formation, which may indirectly affect cancer cells or DTCs residing within the bone marrow niche [33,34]. It was previously reported that blood loss stimulates HSCs and may activate osteoprogenitor cells [35]. Further, Jung et al. [33] demonstrated that HSCs isolated from animals subjected to an acute bleed, showed increased capacity to induce osteoblastic differentiation, due to increased HSC-derived BMP-2 and BMP-6. Later, Shiozawa et al. [36] reported blood loss induced Epo production, causing BMP production in HSCs through a Jak/Stat signaling mechanism. In addition Epo regulates the bone microenvironment through direct action on mesenchymal cells, inducing osteoblast differentiation. Thus demonstrating that Epo can regulate bone metabolism through induction of osteoblast differentiation or production of BMPs by HSCs [34,36]. Further investigation showed increased angiogenesis as well as elevated numbers of red blood cells in the peripheral blood, and mesenchymal cells and hematopoietic stem cells in the bone marrow [34]. Taken together, understanding the role of Epo on the niche, within which DTCs reside may aid in the development of effective treatment modalities for cancer patients. Together these data demonstrate interconnectivity of hematopoiesis and tumor metastasis. On one side the HSC niche is targeted by circulating tumor cells to facilitate the establishment of DTCs in marrow. Once there, DTCs are likely to undergo one of three fate decisions: apoptosis, dormancy or proliferation. Each of these fate choices are likely regulated by the niche by soluble and non-soluble factors. The niche, as an integrator of systemic demands for hematopoiesis, also is likely able to regulate DTC fate when occupied by these molecular parasites. Yet how this occurs, remains poorly understood. Similarly, progeny of DTCs are able to produce osteoblastic, osteolytic lesions or mixed. How this occurs is also not well understood and how the niche participates or regulates these activities is an active area of investigation (Fig. 1).