The Role of the IGF Axis in Epithelial-to-Mesenchymal Transition during the Progression of Prostate Cancer

Abstract

Prostate cancer is the second most common lethal cancer in men worldwide. Despite the fact that the prognosis for patients with localized disease is good, many patients succumb to metastatic disease with the development of resistance to hormone treatments. This is normally termed castration-resistant prostate cancer (CRPC). The development of metastatic, castration-resistant prostate cancer has been associated with epithelial-to-mesenchymal transition (EMT), a process where cancer cells acquire a more mesenchymal phenotype with enhanced migratory potential, invasiveness and elevated resistance to apoptosis. The main event in EMT is the repression of epithelial markers such as E-cadherin and upregulation of mesenchymal markers such as N-cadherin, vimentin and fibronectin. The insulin-like growth factor (IGF) signalling axis is essential for normal development and maintenance of tissues, including that of the prostate, and dysregulation of this pathway contributes to prostate cancer progression and malignant transformation. It is becoming increasingly clear that one of the ways in which the IGF axis impacts upon cancer progression is through promoting EMT. This review will explore the role of EMT in prostate cancer progression with a specific focus on the involvement of the IGF axis and its downstream signalling pathways in regulating EMT in prostate cancer.Keywords: Epithelial-to-mesenchymal transition, insulin-like growth factor family, prostate cancer progression, lifestyle factors. PROSTATE CANCERProstate cancer is the second most common lethal cancer diagnosed in men. According to The American Cancer Society, it is estimated that more than 220 000 new cases of prostate cancer will occur in the United States during 2015 accounting for about 26% of all cancers in men with a mortality rate of 9%: the second highest cause of cancer deaths in men after lung cancer [1].Age is the biggest risk factor for PCa with the incidence of prostate cancer being higher in older men particularly in men aged 65 and above [2]. The incidence of, and mortality from, prostate cancer varies hugely within different racial and ethnic groups. Much higher incidence and death rates are reported in black men compared to other races [3,4]: the reasons underlying these observations are still unclear but both genetic and/or environmental influences may be involved. A number of epidemiology studies have also reported that family history is a risk factor for PCa-with approximately 5-10% of cases being attributable to inherited genetic factors or PCa susceptibility genes [5,6] The prognosis for patients with localized disease is good, however the morbidity and mortality for prostate cancer patients who develop metastatic disease is high [7]. Androgen deprivation therapy (ADT) which involves surgical or chemical castration plays an important role in the treatment and management of prostate cancer and is also utilised as an adjuvant or neo-adjuvant treatment for high-risk disease [8]. The response to the treatments is however temporary a...

Systemic Metabolism, Its Regulators, and Cancer: Past Mistakes and Future Potential

“…This phenotypic switch results in loss of the tight cell-cell adhesion characteristic of epithelial cells and gain of a mesenchymal phenotype characterized by increased motility and invasiveness; facilitating the progression to metastatic disease. Accumulating evidence indicates a role for the insulin/IGF-axis in regulating EMT (71, 72). In relation to this epithelial plasticity two recent studies have also both reported that activation of PI3K can result in de-differentiation of lineage restricted mouse mammary epithelial cells into multipotent stem-like cells that can then differentiate into mixed lineage cells resulting in heterogeneity in subsequent tumors (73, 74).…”