Currently, Prostate cancer (PCa) is considered the most common nonmelanoma neoplasia among men, classified as hormone-related cancer, is a complex multifaceted and biologically heterogeneous disease. 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. 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 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 and a Dietary chemoprevention as potential strategy for preventing cancer development. Recently it has been demonstrated in a number of studies that Natural dietary compounds exhibited several beneficial effects for the prevention of disease and the inhibition of chemically-induced carcinogenesis.
Accumulating evidences suggest that PCa 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.
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, Lycopene, apigenin, Cryptotanshinone), known as STAT3 signalling inhibitors, could be used as chemo-protective agents for pollutants.
The results of these studies, in particular the identification of phytochemicals components, will be a useful contribution to the Ecofoodfertility Project, coordinated by Dr. Luigi Montano (16).The project is a human biomonitoring study ( with multidisciplinary approaches involving, environment, life-style and diet, using the qualitative and quantitative alterations of human semen, as a key to understand both the level of environmental quality and its long term modifications to set out health risks for populations in relation with their living environment as well as diet and lifestyle. The project is underway in the most polluted areas of Italy (Brescia-Caffaro, Val del Sacco in Frosinate, Taranto, Gela, Sassuolo).