Prostate cancer is the second most common cause of cancer and the sixth leading cause of cancer death among men worldwide. The global prostate cancer burden is expected to increase to about 1.7 million new cases and 499,000 new deaths by 2030 simply due to the population expansion and aging.
Radical prostatectomy, radiation therapy that includes external beam radiation therapy, and brachytherapy are the three main treatment options for localized prostate cancer. Although these primary therapies have been shown to have high cancer control rates for localized disease, up to a third of patients undergoing these therapies can have a biochemical recurrence with remaining radioresistance as a major challenge in the treatment of prostate cancer.
Recently, cancer stem cells (CSCs), a subset of cancer cells initiating and propagating tumors, have recently been identified and characterized in prostate cancer. CSCs enable the tumor to grow and metastasize, therefore, eradicating CSCs is expected to provide cancer patients long-term disease-free survival.
Additionally, the CSCs have been demonstrated to be more resistant to chemotherapy and radiotherapy. The CSC theory offers a potential explanation for the relapse and resistance to the therapy occurring in multiple tumors. It hypothesizes that tumors are a heterogeneous cell population, and their growth is driven by a discrete subpopulation of cells-the CSCs. These have abilities of self-renewal and differentiation into multiple cell types, which can produce tumors and also serve as a reservoir of cells that cause tumor recurrence after therapy.
Bao, et al, showed that CD133+ glioblastoma CSCs are more resistant to radiation therapy than non-CSCs. Xiao, et al, demonstrated that CD44 is a CSC biomarker associated with radioresistance in prostate cancer cells. Investigating how CSCs are associated with radiotherapy resistance may help in predicting its occurrence and the development of radiosensitizers specific to prostate cancer.
Epithelial-Mesenchymal Transition
Epithelial-mesenchymal transition (EMT) has been postulated as a mechanism of cancer cells acquiring invasive and stem-like traits necessary for distant metastasis by suppressing their epithelial features and changing to mesenchymal ones. CSCs demonstrating an EMT feature are associated with resistance to drug therapy and radiotherapy as they remain after the cancer treatment, causing recurrence and metastasis.
EMT is characterized by the loss of expression of E-cadherin and, therefore, allows tumor invasion and metastasis. Induction of EMT in tumor cells renders them more resistant to the conventional chemoradiation therapy. Several studies suggested that the PI3K/AKT/mTOR pathway, a major intracellular network proliferating cells, is associated with induction of EMT by upregulating signals, which regulates the self-renewal and migration of CSCs. Understanding the role of CSCs in prostate tumorigenesis and the PI3K/AKT/mTOR signaling pathways promoting prostate CSC maintenance and tumor progression is essential in development of novel therapeutics for prostate cancer and overcoming radioresistance. However, direct evidence for the role of CSC, EMT, and their association with PI3K/AKT/mTOR pathway in newly diagnosed prostate cancer patients remains unclear.
PI3K/AKT/mTOR Pathway
The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is a key signaling pathway that has been linked to both tumorigenesis and development of resistance to treatment in solid malignancies. Physiologically, this pathway has been linked to cell growth, differentiation, proliferation, metabolism, migration, angiogenesis, and survival.
This pathway is negatively regulated by the phosphatase and tensin homolog (PTEN), which dephosphorylates PIP3 to PIP2, thereby terminating further downstream signaling. About 40 percent of prostate cancer exhibits PTEN deletions, silence mutations and loss of function mutations, reducing expression.
Preclinical laboratory data has provided a compelling foundation for studying the role of inhibitors of PI3K and its downstream targets in prostate cancer. Taylor, et al, identified that PI3K pathway showed abnormal signaling in prostate cancer by performing genomic profiling of 218 primary or metastatic prostate cancers. Although activating mutation of the PIK3CA gene is rarely seen in prostate cancer, loss of function mutations are noted to be highly prevalent in the regulatory subunits PIK3R1 and PIK3R3, indicating existence of alternative means of indirect PI3K activation.
Despite the understanding of pathway signaling, the attempt to target segments of the PI3K/AKT/mTOR signaling pathway in prostate cancer patients has shown disappointing outcomes. Single-agent use of the mTOR inhibitors (rapamycin, everolimus, and temsirolimus) or in combination with the androgen receptor antagonist, bicalutamide, has failed to demonstrate clinical activity in metastatic castration-resistant prostate cancer (mCRPC).
Demonstration of chemoresistance reversal through mTOR inhibition in preclinical studies has prompted the designing of clinical trials to examine the efficacy of combined treatment with mTOR inhibitors and docetaxel. Given high alterations in the PI3K/Akt/mTOR pathway components in prostate cancer, not limited to mutations, altered expression, and copy number alterations, it manifests as its increased downstream signaling; decreased expression of the inhibitory PTEN, INPP4B, and PH and leucine-rich repeat protein phosphatase (PHLPP), another negative regulator of Akt; and decreased expression of the PI3K regulatory genes-PIK3R1 and PIK3R3.
Furthermore, androgens increase stress-activated protein kinase-interacting protein 1 in the nucleus that leads to TORC2 stimulation, resulting in Akt activation.
Clinical Importance of Prostate Stem Cells
Human prostate is made with two types of cells: stromal and epithelial cells of which epithelial cells can further be divided into four different subtypes of cells, including basal cells. Prostate stem cells (PSCs) are recognized to be confined in the basal cell compartment of the human prostate. In vitro, human prostate cells with a basal phenotype undergo self-renewal capacity to reconstitute the prostate epithelium containing basal and luminal cells. PSCs are the undifferentiated prostatic basal epithelium that are known to survive in androgen deprivation, responsible for prostatic growth after cessation of therapy.
Prostate-specific membrane antigen has been used as a target of drug therapy and diagnostic imaging as they are highly expressed in PC. PSCs are emerging therapeutic targets of prostate cancer, but identifying those cells and finding the right targetable subtypes of cells are changing. Several studies suggested that basal stem cells expressed specific stem cell markers, such as CD44(+), [alpha]2[beta]1high, CD133(+), ALDHhigh, as the origin of prostate cancer. Glumac, et al, found that CD133, a cell surface antigen, is also highly expressed in certain types of prostate, such as aggressive variant prostate cancer, suggesting it can be a targetable marker in cancer treatment and novel imaging techniques.
VASANTHAN MUTHUSAMY KUMARASAMY, MD, is in the Department of Internal Medicine at the University at Buffalo-Jacobs School of Medicine and Biomedical Sciences. CAROLINE SOOYUN LEE, MD, is in the Department of Hematology and Medical Oncology at the Icahn School of Medicine at Mount Sinai. SANDEEP MITTAN, PHD, FAHA, is in the Division of Medical Oncology at the Montefiore Medical Center and The University Hospital for Albert Einstein College of Medicine, New York.
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