Peroxisome proliferator-activated receptor gamma controls prostate cancer cell growth through AR-dependent and independent mechanisms.

BACKGROUND: Prostate cancer (PC) remains a leading cause of cancer mortality and the most successful chemopreventative and treatment strategies for PC come from targeting the androgen receptor (AR). Although AR plays a key role, it is likely that other molecular pathways also contribute to PC, making it essential to identify and develop drugs against novel targets. Recent studies have identified peroxisome proliferator-activated receptor gamma (PPARγ), a nuclear receptor that regulates fatty acid (FA) metabolism, as a novel target in PC, and suggest that inhibitors of PPARγ could be used to treat existing disease. We hypothesized that PPARγ acts through AR-dependent and independent mechanisms to control PC development and growth and that PPARγ inhibition is a viable PC treatment strategy. METHODS: Immunohistochemistry was used to determine expression of PPARÒ¯ in a cohort of patients with PC. Standard molecular techniques were used to investigate the PPARÒ¯ signaling in PC cells as well a xenograft mouse model to test PPARÒ¯ inhibition in vivo. Kaplan-Meier curves were created using cBioportal. RESULTS: We confirmed the expression of PPARÒ¯ in human PC. We then showed that small molecule inhibition of PPARγ decreases the growth of AR-positive and -negative PC cells in vitro and that T0070907, a potent PPARγ antagonist, significantly decreased the growth of human PC xenografts in nude mice. We found that PPARγ antagonists or small interfering RNA (siRNA) do not affect mitochondrial activity nor do they cause apoptosis; instead, they arrest the cell cycle. In AR-positive PC cells, antagonists and siRNAs reduce AR transcript and protein levels, which could contribute to growth inhibition. AR-independent effects on growth appear to be mediated by effects on FA metabolism as the specific FASN inhibitor, Fasnall, inhibited PC cell growth but did not have an additive effect when combined with PPARγ antagonists. Patients with increased PPARÒ¯ target gene expression, but not alterations in PPARÒ¯ itself, were found to have significantly worse overall survival. CONCLUSIONS: Having elucidated the direct cancer cell effects of PPARγ inhibition, our studies have helped to determine the role of PPARγ in PC growth, and support the hypothesis that PPARγ inhibition is an effective strategy for PC treatment.

Assessment of distress and quality of life in rare cancers.

OBJECTIVE: Rare cancers are a heterogeneous group of conditions that can be associated with emotional and physical impairments. In view of the dearth of research in this area, we investigated the quality of life and prevalence of distress in a cohort of patients diagnosed with a rare cancer, classified by the RARECARE definition. METHODS: A cohort of rare cancer patients, treated in a Brazilian public cancer center, was assessed for distress (Distress Thermometer), anxiety/depression (Hospital Anxiety and Depression Scale), and quality of life (Functional Assessment of Cancer Therapy-General Version). Descriptive statistics were generated, and multivariate analyses were used to identify factors associated with distress, anxiety/depression, and quality of life. RESULTS: A total of 137 patients (52.6% male, mean age of 50 years; range 18-90) were identified. Nearly half (49.6%) of patients reported high levels of distress, with 19.7% endorsing anxiety and 15.3% depression. In multivariate analysis, demographic and clinical variables associated with worse psychosocial outcomes included younger age (P < 0.05), female gender (P < 0.01), advanced disease stage (P < 0.01), and engagement in active therapy (P < 0.05). CONCLUSIONS: Patients diagnosed with rare cancer reported poorer psychosocial outcomes and impaired quality of life when compared to the general population of cancer patients. Certain demographic groups (eg, women and younger patients) may benefit from targeted psychosocial interventions.

Different roles of peroxisome proliferator-activated receptor gamma isoforms in prostate cancer.

Due to the increasing occurrence of and high costs associated with prostate cancer (PC), there is an urgent need to develop novel PC treatment and chemoprevention strategies. Although androgen receptor (AR) signaling is significant in the development and progression of PC, other molecular pathways contribute as well. Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) has recently been implicated as an oncogene in PC, which may influence both the development and metastatic progression of the cancer. There are two isoforms of PPARγ, with PPARγ2 having an additional 30 amino acids at the amino terminus. Here, we investigated the differential expression and function of these two isoforms in benign and cancerous prostate epithelial cells. The findings from our immunohistochemistry (IHC) and RNA in situ hybridization experiments suggest that although both isoforms are expressed in benign human prostate tissue, PPARγ1 predominates in PC tissue. Our results from PC cell line experiments suggest that PPARγ1 contributes to the proliferation of some PC cells and that PPARγ2 represses PC cell growth. Our findings also suggest that PPARγ1 increases the growth and possibly the transformation of otherwise benign prostate epithelial cells. These results help to establish different roles for PPARγ isoforms in prostate cells, and support the hypothesis that PPARγ1 acts as an oncogene and that PPARγ2 acts as a tumor suppressor in prostate cells.

Role of Biomarkers in Prediction of Response to Therapeutics in Metastatic Renal-Cell Carcinoma.

Renal-cell carcinoma remains one of the elusive cancers that lacks a biomarker. It is the eighth most commonly diagnosed malignancy in the United States, and the incidence has slowly trended upward. In addition to the increase in newly diagnosed cases, the prevalence and overall survival of individuals with kidney cancer also has increased substantially. This formal review synopsizes the literature regarding the current treatment landscape, the utility of biomarkers in renal-cell carcinoma, and future directions regarding next-generation sequencing of circulating tumor DNA.

Examining Public Communication About Kidney Cancer on Twitter.

PURPOSE: Several studies have described the content of Twitter conversations about lung, breast, and prostate cancer, but little is known about how the public uses Twitter to discuss kidney cancer. We sought to characterize the content of conversations on Twitter about kidney cancer and the participants engaged in these dialogues. METHODS: This qualitative study analyzed the content of 2,097 tweets that contained the key words kidney cancer from August 1 to 22, 2017. Tweets were categorized by content domain of conversations related to kidney cancer on Twitter and user types of participants in these dialogues. RESULTS: Among the 2,097 kidney cancer-related tweets analyzed, 858 (41.4%) were authored by individuals, 865 (41.2%) by organizations, and 364 (17.4%) by media sites. The most common content discussed was support (29.3%) and treatment (26.5%). Among the 2,097 tweets, 825 were unique tweets, and 1,272 were retweets. The most common unique tweets were about clinical trials (23.9%), most often authored by media sites. The most common retweets were about treatment (38.5%), most often authored by organizations. CONCLUSION: Twitter dialogues about kidney cancer are most commonly related to support and treatment. Our findings provide insights that may inform the design of new interventions that use social media as a tool to improve communication of kidney cancer information. Additional efforts are needed to improve our understanding of the value and direct utility of social media in improving kidney cancer care.