Abstract 3903: Targeting oral cancer stem cells in the hypoxic niche by BCG infected mesenchymal stem cells
Authors: Pal Bidisha , Bhuyan Seema , Garhyan Jaishree , Li Hong , Bhuyan Rashmi , Yeger Herman , Das Bikul 
Published: July 2017

Abstract
Background: Tumor hypoxia is a major contributing factor in cancer therapeutic failure. The microenvironment of hypoxia/oxidative stress may reprogram cancer cells to highly tumorigenic, metastatic, angiogenic and stem cell-like state. We have characterized in vitro and in vivo models of hypoxia-induced cancer cell reprogramming to cancer stem cell (CSCs) like cells including an immunocompetent model of oral cancer. These CSCs exhibit ABCG2 cell surface marker. Numerous approaches including targeted therapy using oncolytic virus and bacteria have been attempted to target cancer cells in their hypoxic niche without major therapeutic success. Major therapeutic challenges include the inaccessibility of hypoxic niche by therapy-agents and the poor replication of viruses or bacteria intracellular to hypoxic cancer cells. Furthermore, the immune privileged microenvironment of tumor hypoxia could pose a challenge to viral/bacterial-induced immunity against the tumor. In this context, here we have tested a novel stem cell-based approach to deliver BCG infected stem cells to the hypoxic core of tumors.
Methods: Human SCC-25 cell line-derived xenograft in NOD/SCID mice exhibit hypoxic zones, where ABCG2+ resides (1). SCC-25 tumor-bearing mice were injected i.v. with CD271+ bone marrow mesenchymal stem cells (BM-MSCs). We recently found that CD271+ BM-MSCs could be infected with M. tuberculosis. The BCG infected CD271+ BM-MSCs were injected to SCC-25 xenograft-bearing mice. The mice were sacrificed on day-20 of stem cell injection and then evaluated for the hypoxic CSCs. Next, we have developed a 4-NQO induced oral cancer cell line, which was injected orthotropic to the tongue of congenic mice. The mice developed tumors, which was hypoxic. In these tumor-bearing mice, BCG-infected murine CD271 BM-MSCs were injected i.v., and animals were monitored for four weeks for tumor growth. On day-20 of injection, mice were sacrificed, and the tumors were collected. In a control group, BCG alone was injected.
Results: In both the SCC-25 and an immunocompetent mouse model, we found that BCG or CD271+ BM-MSCs injection alone did not result in marked anti-tumor activity and or elimination of ABCG2+ cells from their hypoxic niche. In contrast, the injection of BCG infected CD271+ BM-MSCs led to marked reduction of tumor growth. Importantly, we observed marked replication of BCG intracellular to CSCs. These results indicate that CD271+ BM-MSCs facilitated the transfer of BCG to cancer cells residing in the hypoxic zone. Importantly, the transfer of BCG was seen more in the immunocompetent model, suggesting potential role of immune system.
Conclusions: Our findings indicate that hypoxic CSCs may be targeted by a few BCG infected CD271 BM-MSCs. We propose this could be a novel therapeutic approach to target drug resistance cancer stem cells residing in the hypoxic niche of tumors.1. Bhuyan R et al, Cancer Research, 2016; Volume 76, Issue 14 Supplement, pp. 935.
Note: This abstract was not presented at the meeting.
Citation Format: Bidisha Pal, Seema Bhuyan, Jaishree Garhyan, Hong Li, Rashmi Bhuyan, Herman Yeger, Bikul Das. Targeting oral cancer stem cells in the hypoxic niche by BCG infected mesenchymal stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3903. doi:10.1158/1538-7445.AM2017-3903