Official websites use. Share sensitive information only on official, secure websites. Phone: ; Fax: ; E-mail: mmimeault unmc. Consequently, the molecular targeting of these deregulated gene products in the PC- and metastasis-initiating cells and their progenies represent new promising therapeutic strategies of great clinical interest for eradicating the total PC cell mass and improving current antihormonal treatments and docetaxel-based chemotherapies, thereby preventing disease relapse and the death of PC patients.
Prostate cancer PC is among the most commonly diagnosed malignancies and is the second leading cause of cancer-related deaths in men 1 β 6. Although progress in developing early detection tests has led to improved clinical treatments of patients diagnosed with low-grade and organ-confined PCs by radical prostatectomy and radiotherapy, the progression to locally advanced, invasive and metastatic castration-resistant prostate cancers CRPCs usually leads to disease relapse 1 , 2 , 5 , 7 β 9.
In fact, despite the fact that the patients with locally advanced PCs initially respond to androgen deprivation by surgical or chemical castration, androgen-independent AI lesions may eventually develop and progress despite low levels of circulating androgens 9 β The CRPCs are refractory to conventional treatments by anti-hormonal therapy, radiotherapy and chemotherapy 1 β 5 , 7 β 9 , More specifically, the first-line systemic docetaxel-based chemotherapies used as care for the patients with high-risk or metastatic CRPCs are only palliative and typically culminate in the death of patients after about 12β19 months 1 β 3 , 5 , 8 , Numerous investigations have been made to define the molecular transforming events occurring in prostatic epithelial cells and their local microenvironment that may contribute to PC initiation and progression to locally invasive and metastatic disease stages as well as their acquisition of an AI phenotype in humans.
These tumorigenic cascades can account for the sustained growth, survival, invasion, metastases and treatment resistance of PC cells. These fusion genes encode for oncoproteins that can provide key roles for PC progression and treatment resistance 30 β In addition, the changes in the tumor reactive stroma, including the release of different growth factors by activated myofibroblasts, typically take place during PC progression under normoxic and hypoxic conditions and may promote the malignant transformation of PC cells and neoangiogenesis 5 , 11 , 13 , 43 β The provided information should help to design novel effective multitargeted approaches for improving the current anti-hormonal treatments and docetaxel-based chemotherapies to treat the PC patients at early and late stages, including patients with a high risk of disease recurrence or relapse after treatment initiation.
Molecular oncogenic events associated with PC initiation and progression to a locally invasive disease stage and bone metastasis and novel targeting therapies. The activation of metastasis-initiating cells under specific microenvironmental conditions prevalent at bone induced via the release of diverse paracrine growth factors and cytokines by fibroblasts and bone cells, and that is associated with the formation of secondary tumor formation at bone, is also illustrated.
