Chronic inflammation is associated with advanced prostate cancer (PCa), although the mechanisms governing inflammation-mediated PCa progression are not fully understood. PCa progresses to an androgen independent phenotype that is incurable. We previously showed that androgen independent, androgen receptor negative (AR−) PCa cell lines have high p62/SQSTM1 levels required for cell survival. We also showed that factors in the HS-5 bone marrow stromal cell (BMSC) conditioned medium can upregulate p62 in AR+ PCa cell lines, leading us to investigate AR expression under those growth conditions. In this paper, mRNA, protein, and subcellular analyses reveal that HS-5 BMSC conditioned medium represses AR mRNA, protein, and nuclear accumulation in the C4-2 PCa cell line. Using published gene expression data, we identify the inflammatory cytokine, IL-1β, as a candidate BMSC paracrine factor to regulate AR expression and find that IL-1β is sufficient to both repress AR and upregulate p62 in multiple PCa cell lines. Immunostaining demonstrates that, while the C4-2 population shows a primarily homogeneous response to factors in HS-5 BMSC conditioned medium, IL-1β elicits a strikingly heterogeneous response; suggesting that there are other regulatory factors in the conditioned medium. Finally, while we observe concomitant AR loss and p62 upregulation in IL-1β-treated C4-2 cells, silencing of AR or p62 suggests that IL-1β regulates their protein accumulation through independent pathways. Taken together, these in vitro results suggest that IL-1β can drive PCa progression in an inflammatory microenvironment through AR repression and p62 induction to promote the development and survival of androgen independent PCa.
Point-of-care (POC) technologies have proved valuable in cancer detection, diagnosis, monitoring, and treatment in the developed world, and have shown promise in low-and-middle-income countries (LMIC) as well. Despite this promise, the unique design constraints presented in low-resource settings, coupled with the variety of country-specific regulatory and institutional dynamics, have made it difficult for investigators to translate successful POC cancer interventions to the LMIC markets. In response to this need, the National Cancer Institute has partnered with the National Institute of Biomedical Imaging and Bioengineering to create the National Institutes of Health Affordable Cancer Technologies (ACTs) program. This program seeks to simplify the pathway to market by funding multidisciplinary investigative teams to adapt and validate the existing technologies for cancer detection, diagnosis, and treatment in LMIC settings. The various projects under ACTs range from microfluidic cancer diagnostic tools to novel treatment devices, each geared for successful clinical adaptation to LMIC settings. Via progression through this program, each POC innovation will be uniquely leveraged for successful clinical translation to LMICs in a way not before seen in this arena.
It is well established that prostate cancer (PCa) cells hone to, adapt, and thrive in the bone. Importantly, bone metastases are found in over 80% of PCa deaths. Therefore, it is imperative to elucidate and characterize the molecular mechanisms that enable PCa cells to thrive in the bone and resist conventional PCa therapies, such as hormone ablation or anti-androgens. We found that the HS-5 bone marrow stromal cell (BMSC) line, a secretory BMSC line that can support hematopoietic stem cell growth, secretes paracrine factors that induce apoptosis in PCa cells. However a subpopulation of the PCa cells can survive the BMSC-induced death. The surviving PCa subpopulation differentiates into a neuronal morphology and looses androgen receptor (AR) expression, reminiscent of treatment-resistant neuroendocrine PCa. Ideally, the loss of AR would induce PCa cell death; however we observe a concomitant increase in the autophagy-related cell survival protein, p62/SQSTM1, and induction of cytoprotective autophagy. Furthermore, we find that interleukin-1 beta (IL-1β) and IL-6, inflammatory cytokine secreted by HS-5 BMSCs, are sufficient to promote PCa neuronal morphology, reduce AR accumulation, upregulate p62/SQSTM1 levels, and induce autophagy. In addition, genetic silencing of p62/SQSTM1 causes PCa cell death and pharmacological inhibition of cytokine or autophagy signaling attenuates PCa neuroendocrine differentiation. Thus, our PCa-bone marrow stromal cell model suggests that PCa cells can co-opt the immune system in the bone microenvironment leading to PCa androgen independence, treatment resistance, and survival in the bone. Furthermore, our data suggests that inhibiting inflammatory cytokine signaling and/or the autophagy process are rational strategies to combat PCa bone metastasis. Citation Format: Megan Chang, Micaela Morgado, Viral Patel, Michael Gwede, Mary Cindy Farach-Carson, Nikki Delk. Bone marrow stromal cell-secreted inflammatory cytokines promote treatment resistance and survival of prostate cancer cells. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr B15. doi:10.1158/1538-7445.CHTME14-B15
To report our institutional outcomes of patients with non-previously treated, high-risk salivary gland malignancies treated with surgery followed by adjuvant radiation (RT) and chemoradiation (CRT). Materials/Methods: From January 1997 to December 2017, 108 patients were treated with surgery, and adjuvant RT (n Z 50) or CRT (n Z 58) for high-risk pathologic features: perineural involvement (PNI), lymphovascular space invasion (LVSI), positive/close (<2mm) margin, high grade, extracapsular extension (ECE), or positive lymph nodes. Adjuvant RT was delivered in 2 Gy daily fractions, and adjuvant CRT was delivered for 4-6 alternating week cycles: the most common regimen, TFHX, consisted of 5 days paclitaxel (100 mg/m 2 on d1), infusional 5-fluorouracil (600 mg/m 2 / d  5d), hydroxyurea (500 mg PO BID), and 1.5 Gy twice daily irradiation followed by a 9-day break without treatment. The Kaplan-Meier method was used to estimate rates of locoregional control (LRC), disease-free survival (DFS), and overall survival (OS). Regression analyses were used to identify factors associated with LRC, DFS, and OS. Multivariable Cox Regression (MVA) was performed for known confounding risk factors, and factors associated with a trend to significance (p <0.20). Chi-Square was used to compare rates of toxicities between groups. Results: Median follow-up was 52 months (range: 3-226). The most common histologies included: Adenoid Cystic (n Z 30), Mucoepidermoid (n Z 20), and Salivary Duct Adenocarcinoma (n Z 18). The most common location included the parotid (n Z 73). The median RT dose was 66 Gy (range 43.2-74 Gy). The 5-year LRC was 88%, 5-year DFS was 57%, and 5-year OS was 78%. On MVA, LRC was not associated with any factors; DFS was associated with the size of the tumor (HR 2.0, p Z 0.01), tumor location (HR 2.0, p Z 0.01), and stage (HR 1.7, p Z 0.02); and OS was associated with N stage (HR 2.3, p Z 0.005), LVSI (HR 1.9, p Z 0.012), ECE (HR 1.5, p Z 0.032), and stage (HR 1.3, p Z 0.05). CRT was not associated with improved LRC (HR 0.5, p Z 0.34), DFS (HR 0.4, p Z 0.44), or OS (HR: 0.46, p Z 0.384). Since 87% of node positive patients were treated with adjuvant CRT compared to 13% with RT, therefore comparison was not possible. There was no difference in any acute or late grade 3+ toxicities, or parenteral nutrition between RTand CRT (p Z 0.98, p Z 0.85, and p Z 0.83), respectively. There was one acute grade 5 toxicity in the RT group. Conclusion: To our knowledge, this is the largest single institution cohort of adjuvant CRT for high-risk salivary malignancies. Overall, adjuvant CRT doesn't enhance outcomes compared to adjuvant RT alone. However, LRC was similar between RT and CRT groups in spite of more adverse features (nodal disease and ECE) in the CRT group. Distant metastatic disease remains a significant pattern of failure. We await large prospective evidence to determine which subsets of patients benefit from adjuvant CRT.
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