Oncogenic activation in prostate cancer progression and metastasis: Molecular insights and future challenges

Abstract

Prostate cancer is a leading cause of death among men in the United States, and currently early diagnosis and appropriate treatment remain key approaches for patient care. Molecularly prostate cancer cells carry multiple perturbations that generate malignant phenotype capable of uncontrolled growth, survival, and invasion-metastasis to other organs. These alterations are acquired both by genetic and epigenetic changes in tumor cells resulting in the activation of growth factor receptors, signaling proteins, kinases, transcription factors and coregulators, and multiple proteases required for the progression of the disease. Recent advances provide novel insights into the molecular functions of these oncogenic activators, implicating potential therapeutic targeting opportunities for the treatment of prostate cancer.

Keywords: PI3K-Akt; Prostate cancer; growth factor receptors; oncogene; proteases; signaling pathways.

Figure 1

Multistep metastatic process of prostate cancer cells. The molecular basis of tumor progression depends on local invasion, intravasation, survival in the circulation, extravasation and colonization. Tumor cells secrete several factors including proteases like MMPs and plasmin which degrade extracellular matrix facilitating their migration and invasion. Tumors cells then intravasate through the endothelial lining of blood vessels into the circulation, and extravasate to distant organs like lymph nodes, bones and rectum. Prostate cancer cells then colonize and proliferate in foreign tissue thereby spreading the disease. (Taken from Dasgupta S, Ph.D thesis,[58])

Figure 2

Cellular localization of various oncogenes and their signaling network promoting growth and survival of prostate cancer cells. Overexpressed growth factor receptors on ligand binding activate PI3K which converts PIP2 to PIP3. Phosphoinositide dependent kinase (PDK1) then binds to PIP3 and phosphorylate Akt. In prostate cancer, loss of PTEN, a lipid phosphatase responsible for converting PIP2 back to PIP3 favors in constitutively activated Akt which then phosphorylates and activates broad range of transcription factors including AR. Activated AR translocates to the nucleus and recruits general transcription factors, coativators (SRC), and other transcription machinery at the target gene promoter enhancing growth, survival and invasiveness. Fused oncogenes like ERG, an AR target gene can also upregulate expression of several genes promoting prostate cancer progression.