Metastasis of prostate cancer often results in death of the patient. A cluster of fatty acid-binding protein (FABP) genes involved in transportation, accumulation and utilization of fatty acids are co-amplified and preferentially expressed in metastatic prostate cancer compared to localized disease. These genes, namely FABP12, FABP4, FABP9, FABP8 and FABP5, individually and collectively, promote properties associated with prostate cancer metastasis. Levels of these FABP genes may serve as an indicator of prostate cancer aggressiveness, and that inhibiting the action of FABP genes may provide a new approach to prevent and/or treat metastatic prostate cancer.
Prostate cancer (PCa) is ranked as the second most frequent cancer and the fifth leading cause of cancer deaths in men worldwide. In 2018, there were ~1.3 million new cases of PCa and 359,000 associated deaths . Localized low grade PCa tumors can usually be successfully treated; however, metastatic PCa is resistant to treatment, resulting in relapse and death . The most common sites of PCa metastasis are the bones and lymph nodes, although metastasis also occurs in lung and liver . The exact mechanisms of PCa metastasis are currently unknown, although a number of key players in metastasis have been investigated . The first step in metastasis is local invasion whereby the invasive cells reduce their cell–cell and cell–matrix adhesive characteristics and acquire the ability to migrate and break down the extracellular matrix (ECM). Breaching the endothelial barriers allows the cancer cells to enter the vascular or lymphatic circulation. Cells can then extravasate and transmigrate through the endothelial layer to reach the interstitium, where, if the environment is favorable, they proliferate and produce a metastatic tumor . It is critical that biological factors and pathways that drive PCa metastasis be identified and studied, to allow precise clinical intervention.
Three features affect the clinical management of PCa. First, PCa is highly heterogeneous, making it difficult to predict response to treatment. Second, as there is an overall lack of molecular signatures to stratify tumor subtypes, treatment is almost exclusively based on histological architecture (Gleason score) , prostate-specific antigen (PSA) levels  and local disease state (TNM, WHO 2009) . Third, unlike other cancers which are characterized by increased glucose consumption and elevated energy production from glycolysis, PCa shows reduced glycolysis and mainly relies on fatty acid oxidation for its energy supply .
FAs are hydrophobic molecules that require fatty acid-binding proteins (FABPs) for their intracellular trafficking . FABPs therefore regulate the cellular accumulation, distribution, utilization and fate of FAs . There are ten FABPs, with each FABP displaying distinct tissue distribution and ligand preference . FABPs are receiving increasing attention in oncology because of their emerging roles in the prevention and treatment of cancer . In particular, FABPs are implicated in metastatic progression in various cancers , including prostate cancer . They are also recognized as important factors in metabolic diseases , particularly as related to PPAR (peroxisome proliferator-activated receptor) function .
Chromosome 8q21 is the most commonly amplified region in PCa metastases . We previously identified a novel fatty acid-binding protein gene, FABP12, in this region (8q21.13), located within a cluster of four other members of the FABP family (FABP4, FABP5, FABP8/PMP2 and FABP9) . Roles for these FABPs in PCa progression have been reported, especially through the modulation of lipid metabolic pathways and metastatic transformation. This review aims to decipher how FABPs, through unique, synergetic or combinatorial actions, can affect PCa invasion and metastasis.
2. Fatty Acid-Binding Protein (FABP) and Prostate Cancer
Metastasis is a multistep process that involves many molecular and physiological alterations. Studies of the FABP cluster on chromosome 8 support a common role for all five FABPs in promoting PCa aggressiveness and metastasis. However, the biological actions of these FABPs appear to be synergic rather than redundant (Figure 1). FABP4 mainly functions as a secreted protein which mediates cancer cell–microenvironment interactions . FABP5 mainly affects de novo fatty acid synthesis, lipolysis and angiogenesis pathways , whereas FABP12 induces EMT and oxidative phosphorylation . PPARs are important mediators of FABP functions presumably through fatty acid transfer from FABPs to PPARs, although the details remain elusive. As well, further studies are needed to determine the precise role of FABPs in modulating lipid metabolism reprogramming and lipid-derived bioenergetics during metastasis. Future in-depth investigations on the cross-talk between fatty acid-FABP-PPAR and androgen-AR signaling pathways may shed light on the mechanism underlying castration resistance and metastasis in PCa. It will be important to further explore the roles of these FABPs in chemotherapy drug resistance in relation to FABP-induced lipid metabolism alterations. As well, it will be interesting to address the role of FABPs in the homing of prostate cancer cells to metastatic sites. Such a role for FABP4 has previously been described for the homing of ovarian cancer cells to omental adipose tissue .
Figure 1. Schematic illustration of the molecular pathways underlying the roles of FABPs co-amplified in PCa. We propose that each FABP contributes to critical processes (e.g., epithelial-to-mesenchymal transition (EMT), cell migration/invasion, FA uptake/synthesis, energy metabolism and angiogenesis) that leads to metastatic progression. The fatty acid-activated nuclear receptors (PPAR β/δ and PPARγ) serve as key mediators in FABPs’ pro-metastatic functions in PCa. Downstream effectors of PPARs are shown in ovals. Stars denote activation of PPARs. Broken lines indicate unproved functions.
As FABPs induce lipid metabolism reprogramming in cancer cells, a property associated with cancer stemness, FABPs may also affect response and resistance to therapy. In fact, FABP5 inhibitors have been reported to synergize with chemotherapy drugs (docetaxel and cabazitaxel) to inhibit PCa growth in vitro and in vivo . Carefully designed PCa patient cohort analyses will be needed to determine whether FABPs, singly or in combination, can serve as predictive biomarkers for anti-tumor therapies. Importantly, FABPs, including FABP4, FABP5, FABP9 and FABP12, have all been shown to have significant prognostic value in PCa patient populations . Whether any of these FABPs, singly or in combination, could be used as independent prognostic biomarkers remains to be seen. The unique influence of lipid metabolism on PCa progression, the preferential amplification and enrichment of FABPs in metastatic PCa and the recent in vitro and in vivo evidence showing their emerging roles in promoting PCa metastasis and progression all point to FABPs as being valid therapeutic targets for advanced PCa carrying this amplified FABP cluster. Initial studies have shown that either a small molecule inhibitor of FABP5/7 (SBFI-26) or a mutated recombinant FABP5 construct (dmrFABP5) exhibit potent inhibitory effects on tumorigenesis and metastasis in xenograft animal models of PCa . These promising results, combined with the documented roles of FABPs in cancer progression, support further development of FABP-targeted inhibitors and therapies for the treatment of PCa.
The entry is from 10.3390/cancers12123823
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