Prostate cancer (PCa), classified as hormone-related cancer, is a complex multifaceted and biologically heterogeneous disease. At the initial stages, PCa cells are dependent on androgens for their growth and hence effectively combated by androgen deprivation therapy (ADT) until PCa recurs during hormonal therapy and became hormone refractory or castration-resistant prostate cancer (CRPC). Although the role of androgen receptors (AR) signalling in PCa development and progression has been well established, the intrinsic heterogeneity of PCa is due to the presence of additional signalling pathways. These include citokines, growth factors and oxidative stress response, which can modulate the AR pathway. Thus, the onset, progression and hormone-resistance of PCa can be triggered by cellular responses to autocrin and paracrin stimuli, as well as environmental factors, which are able to modulate cell activity. Environmental contamination plays an important role in cancer initiation and progression. Organochlorine pesticides (OCPs), such as beta-hexachlorocyclohexane (ß-HCH), are lipophilic and stable compounds, which are also endocrine-disrupting chemicals (EDCs). Human exposure to EDCs is considered a possible cause for hormone dependent tumours. Different metabolic pathways are often modified in PCa cells to preserve cell division and growth, and are related to the malignancy degree. PCa cells associated to high Gleason score tissues mostly show a metabolic shift, with the production of lactate (Warburg effect). Also OCPs can modulate cellular metabolism and then contribute to the transformation of tumour in a more aggressive form. For this reason we decided to study how OCPs, with a particular attention to ß-HCH, can induce a metabolism shift likely involved in chemo-resistance and in hormone refractory of PCa. Understanding the mechanisms of resistance that cause hormone-naive prostate cancer to progress to castration-resistance is the key to develop future therapies.
Accumulating evidences suggest that PCas represent a group of histologically and molecularly heterogeneous diseases with variable clinical courses. Certain risk factors have been identified (age, family history, ethnic origin), but the aetiology of this cancer remains largely unknown. However, a role for environmental factors is strongly suspected. There has been a keen interest in studying the association between PCa and the exposure to environmental chemicals, especially those that mimic androgen or can influence the signaling pathways in human cells. The common consequence of an endocrine disrupting chemical exposure is that it may have an impact on PCa etiology by stimulating both the development as well as the progression into a castration-resistant or hormone-refractory prostate cancer (CRPC).
Prostate cancer, especially as locally advanced and metastatic disease, continues to be a burden on the healthcare system. While the prognosis is good for men diagnosed with a localized disease, the prognosis remains poor for more advanced disease. All current therapies, from androgen deprivation therapy (ADT) to chemotherapy, merely slow the progression of the disease, but all patients inevitably progress on therapy. ADT, the standard care for patients with biochemical recurrence after definitive primary therapy, locally advanced disease or metastatic disease, has been demonstrated to provide an initial benefit, but the majority of patients will progress on CRPC within 2-3 years.
Most of the mechanisms leading to CRPC are mediated by AR or by the androgen axis, which continues to play an important role in the function and growth of CRPC. However, it is necessary to clarify if other pathways, as well as pollutant agents, can contribute to castration-resistance. During the transition from the hormone naïve into CRPC, the progression of PCa cells can be driven by alternative (non-androgen) signalling pathways as JAK/STAT3 pathway. Literature data testify that AR and JAK/STAT3 pathways are functionally synergistic in the progression of PCa. Our previous study demonstrated that STAT3 is a hub protein in cellular signaling pathways triggered by ß-HCH, a widely common pollutant. We hypothesizes the involvement of STAT3, through both its canonical and non-canonical pathways, in response to ß-HCH. STAT3 can be considered a pleiotropic modulator of these signaling pathways and a master regulator of energy metabolism involved in the onset of CRPC.
Our studies, will focus on the understanding of non-androgen signaling pathways and may provide opportunities in the development of novel drugs and therapy strategies targeting CRPC. We hypothesize that a biochemical circuit between pollutants, STAT3 signaling, metabolic enzymes (PKM2, SHMT2) and transcription factors (HIF-1, PKM2), is the cellular process that triggers the first phase of hormone refractory and chemo-resistance phenomenon in PCa. Studies will be performed both on different prostate cell lines, characterized by a different degree, and on FFPE tissues, obtained from prostatectomies. Moreover, a number of patients will be selected from territories contaminated by pollutants, as the "Valle del sacco river" near Rome. In this case, ß-HCH as well as other organochlorines levels will be determined in plasma of selected patients.
Such new information could allow us to expand the pharmacological, diagnostic and prevention strategies. In fact all the proteins of the biochemical circuit proposed represent potential pharmacological targets and diagnostic markers. Furthermore, natural substances (i.e curcuma, caryophyllene, silibinin), known as STAT3 signalling inhibitors, could be used as chemo-protective agents for pollutants.