Cancer stem cells (CSC) maintain both undifferentiated self-renewing CSCs and differentiated, non-self-renewing non-CSCs through cellular division. However, molecular mechanisms that maintain self-renewal in CSCs versus non-CSCs are not yet clear. Here, we report that in a transgenic mouse model of MYC-induced T-cell leukemia, MYC, maintains self-renewal in Sca1 þ CSCs versus Sca-1 À non-CSCs. MYC preferentially bound to the promoter and activated hypoxia-inducible factor-2a (HIF2a) in Sca-1 þ cells only. Furthermore, the reprogramming factors, Nanog and Sox2, facilitated MYC regulation of HIF2a in Sca-1 þ versus Sca-1 À cells. Reduced expression of HIF2a inhibited the self-renewal of Sca-1 þ cells; this effect was blocked through suppression of ROS by N-acetyl cysteine or the knockdown of p53, Nanog, or Sox2. Similar results were seen in ABCG2 þ CSCs versus ABCG2 À non-CSCs from primary human T-cell lymphoma. Thus, MYC maintains self-renewal exclusively in CSCs by selectively binding to the promoter and activating the HIF2a stemness pathway. Identification of this stemness pathway as a unique CSC determinant may have significant therapeutic implications.

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Bone morphogenetic proteins (BMPs) regulate cell fate during development and mediate cancer progression. In this study, we investigated the role of BMP4 in proliferation, anoikis resistance, metastatic migration, and drug resistance of breast cancer cells. We utilized breast cancer cell lines and clinical samples representing different subtypes to understand the functional effect of BMP4 on breast cancer. The BMP pathway was inhibited with the small molecule inhibitor LDN193189 hydrochloride (LDN). BMP4 signaling enhanced the expression of stem cell genes CD44, ALDH1A3, anti‐apoptotic gene BCL2 and promoted anoikis resistance in MDA‐MB‐231 breast cancer cells. BMP4 enhanced self‐renewal and chemoresistance in MDA‐MB‐231 by upregulating Notch signaling while LDN treatment abrogated anoikis resistance and proliferation of anoikis resistant breast cancer cells in the osteogenic microenvironment. Conversely, BMP4 downregulated proliferation, colony‐forming ability, and suppressed anoikis resistance in MCF7 and SkBR3 cells, while LDN treatment promoted tumor spheroid formation and growth. These findings indicate that BMP4 has a context‐dependent role in breast cancer. Further, our data with MDA‐MB‐231 cells representing triple‐negative breast cancer suggest that BMP inhibition might impair its metastatic spread and colonization.

Paragangliomas are rare neuroendocrine neoplasms arising in extra-adrenal chromaffin cells of autonomic nervous system and histologically akin to chemodectomas. They are rare, affecting about 1 in 2,000,000 population. It is a generic term applied to tumors of paraganglia regardless of the location. In rare instances, paragangliomas present around and involve the pancreas, thereby mimicking any one of the more common primary pancreatic lesions. Pancreatic paraganglioma is an extremely rare tumor. It grows slowly, so radical resection is recommended to achieve curability with good prognosis. These neoplasms present considerable diagnostic difficulty not only for the clinician and radiologist but also for the pathologist. Here, we report a case of a 55-year-old woman who presented with a left-sided abdominal swelling for 3 months duration, initially having clinical suspicion of an ovarian tumor. The radiological imaging revealed a lesion in the tail of pancreas with a differential diagnosis of pancreatic carcinoma and metastatic tumor. Only after exploratory laparotomy, the diagnosis was made as a rare case of pancreatic paraganglioma on the basis of histological examination and immunohistochemistry.

The mechanism of tumor hypoxia induced reprogramming of cancer cells are not understood well. Hypoxia might activate evolutionary preserved cellular defense mechanism that could contribute to tumor progression and metastasis. We recently described that during hypoxia/oxidative stress, human embryonic stem cells (hES) exhibit an altruistic defense mechanism, where a few cells reprogram to a highly undifferentiated state, and secrete glutathione to protect rest of the community of cells from oxidative stress induced DNA damage (Das B et al, Stem Cells, 2012). The altruistic stem cells phenotype exhibited high HIF-2alpha and low p53 activity. After a few weeks, the reprogrammed cells, although highly fit to survives, underwent spontaneous apoptosis/differentiation by re-activating the p53/MDM2 oscillation. Thus, the reprogrammed cells sacrificed its own fitness to enhance the fitness of the rest of the community, an altruistic behavior (Das B et al. Stem Cells, 2012). Here, we investigated the potential hijacking of the altruistic defense mechanism by oral cancer cells during exposure to hypoxia. We exposed the four oral cancer cell lines SCC-25, SCC-15, SCC-9 and SCC-5 to extreme hypoxia followed by re-oxygenation for 72 hours. We found that while majority of cancer cells underwent apoptosis, a few cancer cell lines survived, exhibited side-population (SP) phenotype, high level of HIF-2alpha, Nanog, Sox-2 and MYC. The SP cells exhibited migratory activity, as well as high tumorigenic and metastatic activity in NOD/SCID mice. ChIP assay indicated that HIF-2alhpa interact with MYC and NOTCH1. The conditioned media of SP cells exhibited high level of glutathione, and ability to protect non-SP cells from cisplatin-induced toxicity. These results indicate that HIF-2alpha and MYC may cooperate to reprogram a few oral cancer cells to altruistic stemness phenotype. The altruistic phenotype that exhibited cytoprotective activity against cisplatin mediated toxicity. Thus, similar to bacteria, where altruistic biofilm exhibit novel drug resistance mechanism, stem cell altruism may serve as a novel drug resistance mechanism in oral cancer. Citation Format: Rashmi Bhuyan, Hong Li, Sukanya Gayan, Bidisha Pal, Reza Bayat-Mokhtari, Jyotirmoy Phukan, Debabrata Baishya, Anupam Sarma, Joyeeta Talukdar, Manaf Muhammad Alkurdi, Wael Tasabehji, Seema Bhuyan, Gayatri Gogoi, Ista Pulu, Herman Yeger, Bikul Das. Oral cancer cells may hijack stem cell altruism to survive during extreme hypoxia, and exposure to chemotherapeutic drugs. [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 935.

to therapy. Current routine clinical management of BC relies on the availability of robust clinical and pathological prognostic and predictive factors to support patient decision-making in which potentially suitable treatment options are increasingly available. The traditional staging on the basis of tumor size and lymph node status remains the cornerstone of outcome indicators; it has become clear that not all BC s presenting at the same stage have the same underlying biology or clinical behavior. [2] Prognosis varies with tumor size, axillary lymph node status, histologic grade, histologic type and biologic markers such as estrogen receptor (ER), progesterone receptor (PR), Her2/Neu expression profile. [3] Recently

Background: There are various patient and professional factors responsible for the delay in start of treatment (SOT) for head and neck cancers (HNC). Materials and Methods: This retrospective study was conducted on data for HNC patients registered at the hospital cancer registry in North-East India. All cases diagnosed during the period of January 2010 to December 2012 were considered for the present analysis. Educational levels of all patients were clustered into 3 groups; illiterates (unable to read or write), qualified (school or high school level education), and highly qualified (college and above). Results: In the present analysis 1066 (34.6%) patients were illiterates, 1,869 (60.6%) patients were literates and 145 (4.7%) of all patients with HNC were highly qualified. The stage at diagnosis were stage I, seen in 62 (34.6%), stage II in 393 (12.8%), stage III in 1,371 (44.5%) and stage IV in 1,254 (40.7%) . The median time (MT) to the SOT from date of attending cancer hospital (DOACH) was, in illiterate group MT was 18 days, whereas in the qualified group of patients it was 15 days and in the highly qualified group was 10 days. Analysis of variance showed there was a significant difference on the mean time for the delay in SOT from DOACH for different educational levels (F=9.923, p=0.000). Conclusions: Educational level is a patient related factor in the delays for the SOT in HNCs in our population.