Abstract 920: Migratory cancer side population cells induces stem cell altruism in bone marrow mesenchymal stem cells to resist therapy, and enhance tumorigenic potential of non-tumorigenic cells

Abstract

Stem cell may exhibit altruistic behavior that may benefit cancer cells. We recently demonstrated altruistic phenotype in human embryonic stem cells (Das B et al. Stem Cells 2012). The phenotype exhibited reversible induction of high HIF-2alpha and low p53 expression, associated with high glutathione secretion. We speculated that cancer stem cell might induce a similar altruistic phenotype in human bone marrow (BM) derived stem cells (hematopoietic, mesenchymal and endothelial cells). The altruistic reprogrammed BM cells may then facilitate tumor growth, as well as resist the toxicity of oxidative-stress inducing anti-cancer agents. To investigate this possibility, we have obtained conditioned media (CM) from migratory side-population (SPm) and non-SP cells of a diverse panel of tumors including epithelial tumors. The SPm cells exhibit very high tumorigenic capacity (Das B et al, Stem Cell, 2008). The CM was added to in vitro bone marrow (BM) derived CD133+ cells that contain hematopoietic, endothelial, and mesenchymal stem cells. We found that SPm derived CM (henceforth known as SPm-CM) treatment increased the self-renewal capacity of CD271+/CD45- BM-MSCs. Importantly, the reprogrammed CD271+ BM-MSCs (henceforth known as R-MSCs) phenotype exhibited enhanced stemness reprogramming, a cytoprotective mechanism associated with stem cell altruism (Das B et al. Stem Cells, 2012). In contrast, the treatment with CM obtained from non-SP cells did not exhibit R-MSCs. We found that VEGF/VEGR1 autocrine signaling may be involved in R-MSCs mechanism. Importantly, the R-MSCs derived CM reprogrammed non-CSCs to CSCs, and reduced the toxicity of chemotherapy on non-SP cells. In vivo, R-MSCs derived CM, when injected to mice, exhibited mobilization of CD271+ BM-MSCs to circulation. The circulatory CD271+ BM-MSCs exhibited distinct phenotype of R-MSCs including high expression of HIF-2alpha, and VEGFR1. Finally, in human cancer patients, we identified R-MSC phenotype in the peripheral circulation. These studies suggest that cancer stem cells may exploit stem cell altruism to reprogram BM-MSCs for their own benefit. The reprogrammed BM-MSCs gene expression may have the potential as a diagnostic marker for CSC-induced stem cell altruism. Citation Format: Joyeeta Talukdar, Rashmi Bhuyan, Jaishree Garhyan, Bidisha Pal, Sora Sandhya, Sukanya Gayan, Anupam Sarma, Reza Bayat-Mokhtari, Hong Li, Jyotirmoy Phukan, Wael Tasabehji, Seema Bhuyan, Amal Ch Kataki, Rika Tsuchida, Herman Yeger, Debabrata Baishya, Bikul Das. Migratory cancer side population cells induces stem cell altruism in bone marrow mesenchymal stem cells to resist therapy, and enhance tumorigenic potential of non-tumorigenic cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 920.

In vitro Culture of Naïve Human Bone Marrow Mesenchymal Stem Cells: A Stemness Based Approach

“…We reported that pathogen could exploit the stemness of MSC for immune evasion (Das et al, 2013 ; Garhyan et al, 2015 ; Lopes et al, 2016 ). Interestingly, we also found that cancer cells may modulate the stemness of naïve BM-MSCs to favor tumor growth (Talukdar et al, 2016 ; Talukdar et al, under review). These studies further emphasize that naïve MSCs and their stemness may be of importance in the pathogenesis of infectious diseases and cancer.…”

“…Our ongoing study indicates that naïve CD271+ BM-MSCs exhibit anti-tumor activity (Talukdar et al, 2016 ) on migratory cancer side population (SPm) cells, a type of cancer stem cells having high metastatic potential (Das et al, 2008b ). Our findings support previous results that MSCs might exert anti-tumor activity (Khakoo et al, 2006 ; Qiao et al, 2008 ).…”

“…Indeed, we found that the conditioned media of SPm cells could reprogram CD271+ BM-MSCs to ASC like phenotype. These reprogrammed CD271+ BM-MSCs not only exhibited self-sufficiency but also indicated high secretion of VEGF and Stromal derived factor (SDF-1α), another pro-tumorigenic factor (Talukdar et al, 2016 ; Talukdar et al, under review). These reprogrammed CD271+ BM-MSCs or ASCs exhibited high expression of stemness related factors, including Nanog, Sox-2, Oct-4, as well as SSEA3 and CD105.…”

“…Importantly, CD271+ ASCs showed a low p53 protein level, and demonstrated competitiveness in homing to BM in a competitive re-population assay performed in NOD/SCID mice. The homing of CD271+ ASCs facilitated cancer cell growth in the BM (Talukdar et al, 2016 ; Talukdar et al, under review). We like to note that the low p53 state facilitates HSC competition to eliminate competitors in the BM niche (Bondar and Medzhitov, 2010 ).…”

Stem cell basis of a host driven transmission of antigen packed aerosols: a novel mechanism of natural vaccination for tuberculosis

“…The cultures plates were incubated at 37°c for up to 8 weeks and CFUs were counted for all subjects with/without ESPSN. CFUs were plotted as the means of log10 CFUs per mL of the sputum.Assay for VBNC induced MSC to ASC reprograming:The ASC reprograming of VBNC infected MSCs was confirmed as previously described(31,105). Briefly, human CD271+ BM-MSCs were obtained from healthy volunteers after informed consent (1) and infected with VBNC of Mtb-m18b.…”