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Abstract 2681: Oral micro biome enhances stemness in oral cancer cells by activating Toll like receptor signaling

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Abstract

Background: The resistance and progression of cancers after chemotherapy to invasive and metastatic stages accounts for the overwhelming majority of cancer deaths. Recent studies suggest, microbiomes can induce a cascade of host events to either support or inhibit tumor growth. Specially, in oral cancer, chemotherapy treatment may alter the oral microbial flora, which may favor or inhibit tumor growth. Hence, it is importantl to develop novel experimental approaches to study the role of oral microbial flora in oral cancer stemness (self-renewal and undifferntiated state of cancer stem cells). Importantly, patients in developing area, including Assam, where KaviKrishna laboratory is located, may have distinct oral microbial flora that could favor oral cancer growth. Hence, it is important to include patients from developing countries for such studies. Our previous research showed that chemotherapy ehances stemenss in many cancer cell types, including oral squamous cell carcinoma cell line SSC-25. The stemness switch is characterized by enhanced expression of stemness associated genes including Nanog, Lin28A/B, Oct-4, MYC, HIF-2alpha and inflammation associated genes including Toll like receptor (TLR) 2/4. Here we investigated the role of oral microbiomes in the TLR mediated stemness switch of oral cancer cells. Methods: SCC-25 oral cancer cell line was treated with bacterial product lipopoly saccharide (LPS), and the stemness switch evaluated by isolation of ABCG2+ cells and expression of stemness associated genes by these cells. Capacity of interaction of tumor stromal cells with mesenchymal stem cells was also evaluated. Additionally, we obtained sputum from oral cancer subjects undergoing chemotherapy. The patients were from the Kamrup district of Assam, where KaviKrishna laboratory is located. The sputum was processed and then added to the culture medium of SCC-25 cells. These post-sputum treated SCC-25 cells were subjected to phenotypic stemness switch analysis. Results: We found, LPS and sputum treatment led to the enhanced stemness of ABCG2+ cells, including the high expression of TLR2/4, MYC, Nanog, Sox-2, and HIF-2alpha. Importantly, sputum derived from oral cancer subjects under remission showed inhibitory activity on ABCG2+ cell self-renewal. In contrast, sputum obtained from oral cancer subjects with relapse showed enhanced stemness of ABCG2+ cells, and also increased tumorigenic potential. The post-sputum treated ABCG2+ cells exhibited high expression of TLR2/4 and associated increase of HIF-2alpha and MYC transcriptional activity. The sputum treated with broad spectrum antibiotic ciprofloxacin did not enhance the stemness and TLR2/4 signaling of SCC-25 cells. Conclusion: These results indicate that oral microbiomes may differentially influence the stemness of oral cancer cells. We also conclude that live bacteria present in the sputum may be required to enhance stemness in a TLR2/4 dependent manner. Note: This abstract was not presented at the meeting. Citation Format: Joyeeta Talukdar, Rashmi Bhuyan, Bidisha Pal, Sorra Sandhya, Hong Li, Seema Bhuyan, Sukanya Garhyan, Debabrat Baishya, Anupam Sarma, Jyotirmoy Phukan, Amal Kataki, Bikul Das. Oral micro biome enhances stemness in oral cancer cells by activating Toll like receptor signaling [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 2681. doi:10.1158/1538-7445.AM2017-2681

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Cancer stem cells (CSCs) reside in their tumor microenvironment (TME) niches, which are often hypoxic. Previously, we found that hypoxia and oxidative stress prevalent in TME may reprogram CSCs to a highly aggressive and inflammatory phenotype, the tumor stemness switch (TSS) phenotype. We previously reported a “stem cell niche defense” mechanism in bone marrow and lung mesenchymal stem cell niche against pathogen. Pathogen induced bystander apoptosis (PIBA) of stem cells harboring intracellular pathogen may be part of this defense mechanism. We speculate that the TSS phenotype may also activate this niche defense mechanism to defend their TME niche against pathogen and therefore could be exploited to target CSCs. Here we report that CSCs of TSS phenotype enriched in post-hypoxia ABCG2+ CSCs of several cell lines of diverse tumors including oral squamous cell carcinoma cell line SCC-25 exhibited bystander apoptosis when infected with either Bacillus Calmette Guerin (BCG) or mutant Mycobacterium tuberculosis ( Mtb ) strain 18b . The conditioned media (CM) of the infected cells not only exhibited marked anti-tumor activity in vivo, but also showed significant anti-microbial activity. A detailed mechanisms study revealed that some of the infected ABCG2+ CSCs underwent pyroptosis and released a high mobility group box protein 1 (HMGB1)/p53 death signal that can induce a toll like receptor (TLR) 2/4 mediated bystander apoptosis. Thus, our findings suggest that PIBA can be utilized to activate the “niche defense” mechanism in TSS phenotype, which not only target the TSS, but also exhibit marked anti-tumor activity in vivo.
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