The long-standing challenge in the treatment of prostate cancer is to overcome therapeutic resistance during progression to lethal disease. Aberrant transforming-growth factor-β (TGF-β) signaling accelerates prostate tumor progression in a transgenic mouse model via effects on epithelial-mesenchymal transition (EMT), and neuroendocrine differentiation driving tumor progression to castration-resistant prostate cancer (CRPC). Neuroendocrine prostate cancer (NEPC) is highly aggressive exhibiting reactivation of developmental programs associated with EMT induction and stem cell-like characteristics. The androgen receptor (AR) is a critical driver of tumor progression as well as therapeutic response in patients with metastatic CRPC. The signaling interactions between the TGF-β mechanistic network and AR axis impact the EMT phenotypic conversions, and perturbation of epithelial homeostasis via EMT renders a critical venue for epithelial derived tumors to become invasive, acquire the neuroendocrine phenotype, and rapidly metastasize. Combinations of microtubule targeting taxane chemotherapy and androgen/AR targeting therapies have survival benefits in CRPC patients, but therapeutic resistance invariability develops, leading to mortality. Compelling evidence from our group recently demonstrated that chemotherapy (cabazitaxel, second line taxane chemotherapy), or TGF-β receptor signaling targeted therapy, caused reversion of EMT to mesenchymal-epithelial transition and tumor re-differentiation, in in vitro and in vivo prostate cancer models. In this review, we discuss the functional contribution of EMT dynamic changes to the development of the neuroendocrine phenotype—the newly characterized pathological feature of prostate tumors in the context of the tumor microenvironment-navigated cell lineage changes and the role of this neuroendocrine phenotype in metastatic progression and therapeutic resistance.
Kentucky experiences the highest overall cancer incidence and mortality rates in the USA with the greatest burden in the eastern, Appalachian region of the state. Cancer disparities in Kentucky are driven in part by poor health behaviors, poverty, lack of health care access, low education levels, and low health literacy. Individuals with inadequate health literacy are less likely to participate in preventive measures such as obtaining screenings and making healthy lifestyle choices, thus increasing their chances of developing and dying from cancer. By increasing cancer literacy among youth and adults, it may be possible to decrease cancer disparities across Kentucky. This study aimed to establish connections with middle and high schools in Kentucky that would facilitate pilot implementation of a brief cancer education intervention and assessment of cancer health literacy among these student populations. A baseline pretest cancer literacy survey consisting of 10 items was given to 349 participants, followed by the delivery of a cancer education presentation. Immediately following the presentation, participants were given a posttest with identical items to the pretest. Participants were primarily Caucasian (89.4%), female (68.7%), and in 10th through 12th grade (80.5%). Significant (p < 0.0001) increases in both average and median percent of correctly marked items were observed between the pretest and posttest (average, pretest = 56% versus posttest = 85%; median, pretest = 60% versus posttest = 90%). The scores for all individual items increased after the brief intervention. The results demonstrated a significant increase in cancer literacy levels immediately after the pilot educational intervention. We suggest that it may be possible to improve cancer literacy rates in Kentucky by integrating cancer education into middle and high school science and/or health education curricula. This could ultimately drive changes in behaviors that may help lower cancer incidence and mortality rates. Plans for future interventional studies measuring long-term cancer knowledge retention and resultant behavioral changes among middle and high school students as well as the feasibility of integrating cancer education into middle and high school curricula are also discussed.
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