Metabolic reprogramming is an active process occurring in cancer cells, responsible for the rewiring of aerobic glycolysis and oxidative phosphorylation to increase production of antioxidant molecules and biosynthetic intermediates needed for cell growth and proliferation.
Prostate cancer (PC) is the most common malignancy in men and a major cause of death. Starting from the observation that PC cells show specific patterns of metabolic modifications during disease onset and progression, we propose an innovative and ambitious project to identify the molecular basis linking infection, inflammation, and rewiring of cellular metabolism of the prostate. We hypothesize that infection, a common infliction of the prostate causing inflammation, induces remodeling of prostate cell metabolism, leading to a pro-tumoral phenotype, which, in combination with signals coming from the prostate microenvironment, drives cancer development. Our preliminary data provide initial evidence that the link exists, however further studies, including in the context of an in vivo infection model, are needed to identify the key molecular pathways involved. Our results will greatly contribute to launching an unconventional approach linking the non-mutagenic role of infection/inflammation to cancer development.
Genetic mutations are considered to be the main driver of cancer development. Clinical efforts for PC have largely focused on antagonizing genetic modifications, such as those coding for mutated receptors or transduction molecules. These efforts are thwarted by the heterogeneity observed in PC, which does not derive from specific mutations, as shown for other tumors, such as breast cancer [Ford et al., 1998].
Strikingly, however, if one considers prostate cancer from a metabolic point of view, PC cells show specific patterns of metabolic modifications during disease onset and progression. We are convinced that a metabolic approach is the key to effective therapies. It is knwn that soluble signals, such as cytokines (e.g., IL-6), in the PC microenvironment impact PC metabolism [Cutruzzolà et al., 2017], however the role of infection and/or inflammation in this scenario, and its crosstalk with other stimuli, is completely unknown.
We aim to:
Aim 1) establish a role for infection/inflammation in the induction of metabolic alterations in PC cells, by evaluating the cells¿ response to TLR stimulation, using agonists, such as LPS, and prostatitis pathogens, including uropathogenic Escherichia coli;
Aim 2) dissect the interplay among signals from the tumour microenvironment, by studying selected metabolic and signaling pathways in vitro and in a mouse model of prostatitis.
The innovation rests in the concept; no studies have addressed the contribution of bacterial prostatitis to metabolic changes potentially associated with prostate cancer. Cellular metabolism is a relatively new field with much to learn about cells undergoing malignant transformation.
Cutruzzolà, F., G. Giardina, et al., Glucose Metabolism in the Progression of Prostate Cancer. Frontiers in Physiology, 2017. 8(97).
Ford, D., D.F. Easton, et al., Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium. Am J Hum Genet, 1998. 62(3): p. 676-89.