Quantification of Mesenchymal Stem Cells (MSCs) at Sites of Human Prostate Cancer

Abstract

Circulating bone marrow-derived Mesenchymal Stem Cells (BM-MSCs) have an innate tropism for tumor tissue in response to the inflammatory microenvironment present in malignant lesions. The prostate is bombarded by numerous infectious & inflammatory insults over a lifetime. Chronic inflammation is associated with CXCL12, CCL5, and CCL2, which are highly overexpressed in prostate cancer. Among other cell types, these chemoattractant stimuli recruit BM-MSCs to the tumor. MSCs are minimally defined as plastic-adhering cells characterized by the expression of CD90, CD73, and CD105 in the absence of hematopoietic markers, which can differentiate into osteoblasts, chondrocytes, and adipocytes. MSCs are immunoprivileged and have been implicated in tumorigenesis through multiple mechanisms, including promoting proliferation, angiogenesis, and metastasis, in addition to the generation of an immunosuppressive microenvironment. We have demonstrated that MSCs represent 0.01-1.1% of the total cells present in core biopsies from primary human prostatectomies. Importantly, these analyses were performed on samples prior to expansion in tissue culture. MSCs in these prostatectomy samples are FAP-, CD90-, CD73-, and CD105-positive, and CD14-, CD20-, CD34-, CD45-, and HLA-DR-negative. Additionally, like BM-MSCs, these prostate cancer-derived stromal cells (PrCSCs) were shown to differentiate into osteoblasts, adipocytes, & chondrocytes. In contrast to primary prostate cancer-derived epithelial cells, fluorescently-labeled PrCSCs & BM-MSCs were both shown to home to CWR22RH prostate cancer xenografts following IV injection. These studies demonstrate that not only are MSCs present in sites of prostate cancer where they may contribute to carcinogenesis, but these cells may also potentially be used to deliver cytotoxic or imaging agents for therapeutic and/or diagnostic purposes.

Anti-cancer potency of tasquinimod is enhanced via albumin-binding facilitating increased uptake in the tumor microenvironment

“…In this compromised (i.e., stressful) tumor microenvironment, cancer cells initiate adaptive survival pathways and activate an angiogenic switch [2]. Activation of this switch by the cancer cells recruits infiltrating host cells such as endothelial cells, myeloid- derived suppressor cells (MDSCs), macrophages, and bone marrow derived mesenchymal stem cells needed for the chronic stimulation of tumor angiogenesis and cancer cell survival signaling in such a stressful tumor microenvironment [2-6]. Such tumor angiogenesis requires HDAC4 and S100A9 dependent signaling in the cancer cells themselves as well as in the infiltrating host cells [12, 18, 26].…”

“…To continue growth in such a compromised (i.e., stressful) tumor microenvironment, cancer cells must initiate adaptive survival pathways and activate an angiogenic switch [2]. Activation of this switch recruits infiltrating host cells such as endothelial cells, myeloid- derived suppressor cells (MDSC), macrophages, and bone marrow derived mesenchymal stem cells needed for the chronic stimulation of tumor angiogenesis [2-6]. Tasquinimod (ABR-215050; PubChem CID 546828876; CAS number 254964-60-8), Figure 1A, is an orally active quinoline-3-carboxamide which produces robust and consistent in vivo growth inhibition as well as suppression of metastasis in a large series of pre-clinical human xenograft and rodent prostate cancer models [7-12].…”

Cancer exosomes trigger mesenchymal stem cell differentiation into pro-angiogenic and pro-invasive myofibroblasts

“…Their physiological roles include migration into, and repair of inflammatory/injured tissues [18], and some studies aim to manipulate this property as a therapeutic intervention [19]. The intra-tumoural migratory potential of MSC however, has been difficult to assess in humans [20], but migration into tumour xenografts, following intra venous administration has been documented for prostate [21], colon [22], breast [23–24] and other murine cancers models. The presence of MSC in human cancer tissue has certainly been documented, estimating a proportion of < 1.1% of the total cells in prostate for example [21].…”

Prostate cancer exosomes as modulators of the tumor microenvironment

“…MSCs, a multipotent cell type capable of generating many different types of connective tissue, can also differentiate into myofibroblasts in response to secreted factors from tumors [40] . MSCs make up 1.1% of cells within the prostate cancer stroma [59] and exhibit similar tumor promoting effects to cancer associated stroma [40,60,61] .…”