Growth factors involve in cellular proliferation, differentiation and migration during prostate cancer metastasis

Abstract

Growth factors play active role in cells proliferation, embryonic development regulation and cellular differentiation. Altered level growth factors promote malignant transformation of normal cells. There has been significant progress made in form of drugs, inhibitors and monoclonal antibodies against altered growth factor to treat the malignant form of cancer. Moreover, these altered growth factors in prostate cancer increases steroidal hormone levels, which promotes progression. Though this review we are highlighting the majorly involved growth factors in prostate carcinogenesis, this will enable to better design the therapeutic strategies to inhibit prostate cancer progression.

Introduction

Prostate cancer is the second-most common cancer in men of western world [1]. African American and Caribbean men have the highest incidence rates of prostate cancer [2,3]. Current treatment modalities include radical prostatectomy, radiation and hormone therapy have been successful in achieving remission [4,5]. Most of the metastatic tumors after hormonal therapy eventually progress despite castration leading to castration-resistant prostate cancer (CRPC)[6]. Monitoring serum PSA levels and tissue histopathology (Gleason grades) are still useful tool in clinical assessment. Like other tumors metastasis, prostate cancer pelvic lymph node metastasis remains the most significant indicator of patient prognosis and a determinant of therapeutic aggressiveness [7]. Prostate cancer ability to invade the local tissues and to metastasize in different organs, contributes to the ultimate patient morbidity and mortality [8].The absence of effective treatments options for this disease elucidates the importance of development of alternative strategies. There are l apses in the current knowledge of the molecular pathways involved in this progression and such lapses need to be explored in order to develop effective preventive strategies. Role of growth factors in modulating signaling pathways in the development of metastatic prostate cancer is widely accepted [9]. Most of the related signaling pathways include HGF/c-Met, Src kinase, Hedgehog signaling, PI3K/AKT/mTOR, IGF pathway, endothelin axis, SDF-1, Angiogenin, HGF/SF, EGF family, VEGFs, angiogenesis have currently been aiming to create new therapeutic strategies in order to prevent prostate cancer progression [10]. We sought to identify analyzing growth factors and signaling pathways in prostate cancer metastasis and further consolidate their findings, in order to characterize the potential therapeutic targets. This review is an endeavor to highlight these growth factors and their role in prostate cancer metastasis.

Growth factors involved in the metastasis of prostate cancer

Transforming growth factors-β (TGF-β)

Transforming growth factor-beta (TGF-βs) are cytokines that regulate a diverse array of function including cell development, differentiation, angiogenesis, immune response, and inflammation [11]. Dysregulation of TGF-β signaling pathway contributes to a wide range of pathologies including prostate cancer. Despite being a tumor suppressor factor in the normal prostate, growing evidence suggest switching in TGF-β function to promote carcinogenesis [12]. TGF-β performs a lead function in tumor-stroma interactions and promotes the metastatic progression of primary cancer epithelial cells [13]. Elevated TGF-β ligand has also been shown to correlate with the increasing tumor grade in prostate cancer [14]. The induction of TGF-β expression in the stroma activates downstream multifaceted signaling cascades and favors prostate cancer progression via impacting apoptosis, angiogenesis and adhesion [15]. Additionally, a dysfunctional TGF-β receptor signaling advances prostate cancer progression via epithelial-mesenchymal transition (EMT) and cytoskeleton changes in the tumor [16]. Eastham et al., revealed that prostate cancer cells exhibit augmented intracellular and extracellular accumulation of TGF-beta 1 relative to normal prostate tissue and benign prostatic hyperplasia. Moreover, intracellular TGF-beta 1 presence observed in the primary tumor, which is maintained in the metastasis [17]. Tu et al., demonstrated that, transgenic mice expressing a tumorigenic SV40 large T antigen in the prostate along with a dominant negative TGF-β RII mutant signifying interrupted TGF-β signaling in the prostate. Transgenic mice with dysfunctional TGF-β signaling developed increased amount of metastases as compared to the one with normal TGF-β signaling [18]. Furthermore, knocking down of Akt1 in prostate cancer cells, results in increased production of TGF-β1 and its receptor TGF-β RII [19]. It is well known that, EMT plays a significant role in the progression of metastatic castration resistant prostate cancer by inducing TGF [20]. Hu et al., revealed that TGF-β-induced EMT has been linked to increasing Sox5 expression known as transcription factor expressed widely during embryonic development. Thus, patients with high Sox5 expression might be considered relevance to prostate cancer metastasis [21].Report suggested correlation between the preoperative plasma levels of TGF-beta1, interleukin 6 (IL-6), and its receptor (IL-6sR) with prostate cancer progression and metastasis [22]. IL-6 and TGF-beta1 are closely associated with metastatic prostate cancer by analyzing serum levels of these cytokines in patients [23].Based on these finding we may suggest that TGF β is one of the main growth factor in prostate cancer metastasis.

Insulin-like growth factors (IGFs)

The insulin-like growth factor (IGF) plays an important role in normal growth and development by regulating cell proliferation and inhibiting apoptosis IGF includes two other factors termed as IGF-1 and IGF-2. The actions of IGFs are regulated by IGF-binding proteins (IGFBPs) with IGFBP-3 being the prominent binding protein of IGF-1 [24]. IGF-1 mediates its actions via a tyrosine kinase receptor IGF-1 receptor (IGF-1R), which is widely expressed in many cell types including fetal and postnatal tissues [25]. IGF-1 is normally synthesized in the liver but several cancers have been reported as the anomalous source of the polypeptide, proposing that the IGF may carry out through endocrine, paracrine, or autocrine signaling mechanisms at cancer site. IGF-1R. found overexpressed by many tumors including colorectal cancer and melanoma and prostate cancer [26]. Binding of IGF-1 to IGF-1R results in phosphorylation of adaptor proteins, which leads to activation of multiple downward signaling pathways, including PI3K and Ras/Raf/MEK/Erk signaling cascade. These intracellular signals influence; cellular functions, including apoptosis, cell growth, proliferation, and differentiation [27]. Epidemiological studies have established a link between high circulating serum IGF-1 levels and the risk of development of advanced prostate cancer. Additionally, overexpression of IGF-1 in the prostate basal epithelial layer of transgenic mice resulted in prostate adenocarcinoma that was similar to the human disease. Thus, IGF-1 action appears to be important for prostate cancer initiation[28]. Report suggested IGFs induce tumor cell motility via cross-talk between the IGF axis and the integrin system [29]. IGF-1R’s presence has been observed in the normal prostate, prostate cancers as well as metastases [30], and upregulation of IGF-IR signaling axis has been shown to drive the survival of prostate cancer metastases [31]. Hellawell et al., reported the upregulation of IGF-1R at the protein and mRNA level in the primary prostate cancer compared to the normal prostate epithelium in tissue biopsies [32]. Moreover, immunoreactivity of IGF-1R was observed in tumor cells biopsies, which suggested IGF-1R inhibition could be assessed in combination with androgen deprivation therapy(ADT) in patients with metastatic prostate cancer [33]. Chen et al., have shown that IGF-1 increased IL-17 induced expression of VCAM-1 in the vascular endothelial cells which enhances the adhesion of prostate cancer cells with vascular endothelial cells and thus promoting prostate cancer metastasis [34]. Report suggested an association between elevated IGF binding protein-1 and shorter time to CRPC and a lower overall survival in men with metastatic prostate cancer [35]. Insulin-like growth factor-1 genotypes and haplotypes influence the survival of prostate cancer patients with bone metastasis at initial diagnosis [36]. Our study indicated that apigenin effectively suppressed prostate cancer progression in TRAMP mice by attenuating IGF-I/IGFBP-3 signaling and inhibiting angiogenesis and metastasis [37]. The insulin-like growth factor binding protein IGFBP-3 is a pro-apoptotic and antiangiogenic protein in prostate cancer. Report suggest that low IGFBP-3 is associated with greater risk of aggressive, metastatic prostate cancers. It has been reported that mice that are genetically deficient in IGFBP-3 exhibit weaker growth of primary prostate tumors but higher incidence of metastatic disease. Additionally, prostate in IGFBP-3 knockout mice failed to undergo apoptosis after castration [38]. It has been suggested that IGF-II plays an important role in the prostate cancer cell growth in human bone, making it a new therapeutic target for bone metastasis from prostate cancer [39]. Several reports have shown crucial role for IGFBP-2 in the development of androgen insensitivity and the proliferation of androgen independent prostate cancer cells. IGFs and IGFBPs are abundantly present in bone matrix with IGF binding protein 5 (IGFBP-5) as the major IGFBP [40]. These proteins along with prostate-specific antigen reportedly play a major role in prostate cancer bone metastasis. It has been shown that PSA degrades the IGFBP-5 protein in a dose- and time-dependent manner and enhances the bioavailability of IGF in the bone microenvironment of prostate cancer metastasis. Therefore, it permits prostate cancer survival and malignant progression in the bone microenvironment [41]. Based on available reports we may suggest IGFs are important players in metastatic growth of prostate cancer. Dysregulation of IGFs could be detrimental in metastatic progression.

Epidermal growth factor (EGF)

Epidermal growth factor (EGF)-epidermal growth factor receptor (EGFR) signaling has been observed in the progression of prostate cancer [42]. EGFR, a member of the ErbB family of tyrosine kinases, plays a key role in enhancing tumor growth, invasion, and metastasis. The EGFR tyrosine kinase family consists of the following members: EGFR (ErbB1), ErbB2, ErbB3 and ErbB4.EGFR transduces extracellular signals through the activation of intracellular messengers or directly through receptor translocation to the nucleus. It has been suggested that high amounts of EGF are preferentially expressed in poorly differentiated and metastatic tumors as compared to localized and differentiated tumors or normal prostate [43]. EGF and EGF-like ligands bind to EGFR and stimulate cell growth and differentiation. An abnormal EGFR expression in various tumors has been conferred to be associated with an aggressive phenotype and poor prognosis [44]. Under normal circumstances, the availability of EGFR ligands are strictly regulated to match with the tissue’s requirements for homeostasis. However, the sustained production of EGF ligands in the tumor perpetually stimulates EGFR [45]. A mutation in EGFR can also lock the receptor in a state of continual activation [46]. Wang et al. confirmed the role of EGFR using Delta/Notch-like epidermal growth factor (EGF)-related receptor (DNER). It is a neuron-specific transmembrane protein carrying extracellular EGF-like repeats. Silencing DNER in PC-3 cells lead to inhibition of cell proliferation, migration, and invasion of tumorigenesis [47]. Report suggested that growth hormone-releasing hormone (GHRH) reduces the cell adhesion in prostate cancer cells. However, no change in the cell adhesion was observed in PC3 cells to the inhibitors of HER2 or EGFR. Furthermore, the inhibition of EGFR’s action was also found to be associated with decrease in secretion of VEGF [48]. Report suggested the role of EGFR in the expansion of bone tumor in PC-3 M-luc2 bone tumor model; using CXCR4 to transactivate EGFR in PC-3 cells and gefitinib to inhibit the EGFR signaling pathway. Additionally, report suggested that inhibition of the CXCL12/CXCR4 axis through plerixafor abrogates the initial establishment of tumor growth without affecting the growth of established bone tumors, and inhibition of EGFR signaling through gefitinib lead to inhibition of established bone tumor growth [49]. EGFR expression has been linked to primary and secondary sphere formation in prostate cancer cells. Circulating tumor cells (CTC) also represented EGFR expression during prostate cancer metastasis. Further studies suggested that EGFR promoted survival of prostate tumor initiating cells and CTC that metastasize to bone [50]. Tsai et al., reported that EGFR signaling favors metastases of prostate cancer via downregulation of the tumor suppressor ETV6 using microRNA-96 [51].

Hepatocyte growth factor (HGF)

Hepatocyte growth factor/scatter factor ding via (HGF/SF) is a cytokine that plays a critical role in the adhesion, migration, invasion and angiogenesis of tumor cells [52]. Under normal cellular conditions, it is secreted by mesenchymal-derived cells, including dermal and stromal fibroblasts, as a pro-hepatocyte growth factor (HGF) and requires activation by factors such as the HGF activator (HGFA) [53]. HGF mediates its actions via tyrosine kinase receptor c-Met, predominantly expressed on epithelial cells [54]. HGF is involved in many cellular signaling processes viz., proliferation (mitogenesis), motility and tissue regeneration, morphology and differentiation, embryogenesis, angiogenesis, and malignant transformation [55]. Reports suggest that preoperative plasma levels of HGF act as an independent predictor of prostate cancer metastasis to lymph nodes [56]. Over expression of c-Met in prostate cancer is one of the factors for prostate cancer development and progression. HGF stimulation resulted an association between the E-cadherin/catenin complex with the HGF receptor, c-Met, may influence or regulate intercellular adhesion in prostate cancer [57]. Pisters et al. demonstrated that HGF is expressed in human bone stromal cells and is a powerful mitogen to prostatic epithelial cells in culture [58]. Targeting HGF receptor using a hammerhead ribozyme encoding antisense to c-Met, significantly inhibited invasive and migratory potential of prostate cancer [59]. Additional report suggested the expression of c-Met, HGF and its activator and inhibitors follow different patterns in normal cells and cancer cells. The balance between HGF activation and HGF inhibition has been critical for the metastatic potential of the tumor cells [60]. These all reports suggest the role of HGF in metastatic progression of prostate cancer.

Fibroblast Growth Factors (FGFs).

Fibroblast Growth Factor (FGF) family comprises of eighteenligands that act via four signaling tyrosine kinase FGF receptors (FGFRs) [61]. Altered expression of FGF/FGFR signaling has been described in many epithelial cancers including, head and neck, lung, hepatocellular carcinoma, melanoma, breast, bladder, endometrial, and prostate cancer [62]. These FGF ligands exert multiple biological functions, including cellular proliferation, survival, migration, and differentiation using various signaling pathways; RAS/MAP kinase pathway, PI3 kinase/AKT pathway, and PLCγ pathway, RAS/MAP kinase [63]. Prostate cancer epithelial cells express all four types of FGF receptors (FGFR-1 to −4) at a variable frequency. However, majorly FGFR-1 and FGFR-4 expressions closely related to prostate cancer progression, while the role of FGFR-2 is controversial [64]. Normally, prostate stromal fibroblasts secrets FGF-1, but the absence of FGFR-1prevents the abnormal growth of prostate epithelial cells. The gene expression of FGFs, including FGF1 (acidic FGF), FGF2 (basic FGF), FGF6 and FGF8 has shown to be increased in prostate cancer [65]. Presence of FGF’s in cancer cells is further enhanced by their mobilization from the extracellular matrix in cancer tissues. It is suggested FGF2 promotes cell motility and proliferation, increases tumor angiogenesis, and inhibits apoptosis, thus contributing to tumor progression. Polnazsek et al. observed that FGF2-mediated angiogenesis and intranuclear FGF2 activities both play a significant role in prostate cancer progression in vivo [66]. However, irregular aberrant expression of FGFR-1receptor has been found to be associated with prostate cancer [67]. MicroRNA-573 has emerged to be a promising therapeutic target in prostate cancer. miR-573 inhibited prostate cancer cell migration, invasion and TGF-β1-induced EMT. It acts by targeting the FGFR gene and modulating the activation of FGFR1-downstream signaling in response to stimulation by fibroblast growth factor 2 [68]. Immunohistochemical analyses of prostate tissues represented FGF-8 increased expression in prostate cancer epithelium. It has been suggested that FGF8 enhances the growth, invasion and tumorigenesis of the PCa cells. FGF-8 targeted treatment of prostate epithelium has shown to induce prostatic intraepithelial neoplasia in transgenic mice. Furthermore, FGF-8 promoted growth and vascularization in an orthotopic PC-3 model of prostate cancer [69].

Vascular endothelial growth factors (VEGFs)

Once tumor grows beyond 2mm size tumor switches to an angiogenic phenotype and attarcts blood vessels from the surrounding stoma. Angiogenesis has been reported to play an essential role in the growth of solid tumors [70]. Studies have mentioned a correlation between the markers of angiogenesis with metastatic disease, higher Gleason grade and clinical outcomes [71]. The hypoxic micro-environment within prostate cancer promotes upregulation of angiogenesis-associated proteins such as hypoxia-inducible factor 1 alpha and vascular endothelial growth factors (VEGFs) [72]. VEGF has different isoform viz., VEGF-A, -B, -C and – D ligands. These ligands bind to tyrosine kinase receptors viz., VEGFR-1, VEGFR-2, and VEGFR-3. [73]. Reports suggest VEGFR-1 is required for the recruitment of hematopoietic stem cells, migration of monocytes and macrophages [74], whereas VEGFR-2 regulates vascular endothelial function and VEGFR-3 regulates lymphatic endothelial cell function [75]. Binding of VEGF ligands with the corresponding receptors induces receptor dimerization and auto-phosphorylation followed by downstream signaling via secondary messengers including protein kinase and phosphatases supporting a proangiogenic phenotype [76]. Prostate cancer cells express both VEGF-A, B and the VEGF receptor 1 and 2 (VEGFR), which suggests dual signaling pathways involved with autocrine and paracrine mechanisms promoting cell growth and proliferation and angiogenesis respectively. Reports suggest significantly increased levels of VEGF are present in prostate cancers, whereas decreased levels observed in BPH or normal prostate cells [77]. Serum VEGF levels with prostate cancer metastatic disease were found significantly higher than prostate cancer patients [78]. Wang et al., proposed a significant role of VEGF associated vasculogenic mimicry, the formation of fluid-conducting matrix-rich meshwork critical for tumor blood supply, in the development of aggressive and metastatic features [79]. Additionally, therapeutic strategies aimed at preventing angiogenesis have yielded clinical benefits for patients with many different types of cancers [80]. Preclinical findings suggested, potential role of inhibitors in angiogenesis of prostate cancer, which may have significant role in prostate cancer metastatic disease [71]. Published reports indicate VEGF is well recognized in metastatic progression of prostate cancer.

Angiogenin (ANG)

Angiogenin has been identified as a first human derived protein which has in-vivo angiogenic activity [81]. Angiogenin is extremely important for tumor growth in metastatic tumor cells [82]. Report suggested ANG expression stimulated matrix metallopeptidase-2 (MMP2) expression by phosphorylation of ERK1/2. Targeting ANG in vivo with N65828 (a small-molecule inhibitor of the ribonucleolytic activity of human ANG), revealed inhibition of tumor growth, progression and angiogenesis [83]. Moreover, studies have shown that increased expression of angiogenin plays a crucial role in the growth, invasion and metastasis of prostatic adenocarcinoma [84]. Additional report suggested that inhibition of prostate carcinoma metastatic growth in mice by using anti-angiogenin monoclonal antibody (MAb) 26–2F [85]. Another study has shown that targeting angiogenin AUG translation initiation codon region by fully phosphorthioated, particularized JF2S on human prostate tumor metastasis in mice. Therefore we can suggest angiogenin is a valid target against to establish preventative strategies for prostate cancer metastasis [86]. Targeting ANG using ANG inhibitor drugs may have potential to modulate the metastatic progression of cancer.

Stromal cell-derived factor-1 (SDF-1)

Stromal cell-derived factor-1 (SDF-1) receptor also known as CXCL12, binds to its receptor CXCR4 and control cell trafficking of normal and malignant cells. Recent reports suggest that CXCL12 also binds to seven-transmembrane receptor; CXCR7, which is a chemokine play a substantial role in modulating stem cell proliferation and homing of CD34(+) stem cells [87]. Involvement of SDF-1 has been implicated in primary tumor growth and metastasis. It has been reported that CXCR4 expression by tumor cells, plays a significant role in cell metastasis by expressing the ligand SDF-1. Furthermore, CXCR4 overexpression has been linked to poor prognosis in several types of cancer [88]. Report suggested initial establishment of tumors in the bone microenvironment have been linked to]CXCL12 also binds to seven-transmembrane receptor; CXCR7, which is a chemokine play a substantial role in modulating stem cell proliferation and homing of CD34(+) stem cells [87]. Involvement of SDF-1 has been implicated in primary tumor growth by expressing the ligand SDF-1. Furthermore, CXCR4 overexpression has been linked to poor prognosis in several types of cancer [88]. Report suggested initial establishment of tumors in the bone microenvironment have been linked to blocking the CXCL12/CXCR4 axis [49]. The CXCL12-CXCR4 axis enhances epithelial-mesenchymal transition (EMT) by stimulating the extracellular signal-regulated kinase (ERK) 1/2 pathway [89]. Report suggested that phosphatidylinositol 4-kinase IIIα (PI4KIIIα), was identified as a potential regulator of CXCR4 by inducing prostate cancer cell invasion and aggressiveness [90]. It has also been suggested that CXCL12/CXCR4 signaling activates Akt-1 and MMP-9 expression in prostate cancer cells. These findings have been linked tumor cells growth in the bone matrix [91].The SDF-1/CXCR4 pathway regulated angiogenesis by altering proangiogenic and antiangiogenic growth factors in prostate cancers [92]. Data suggest that.overexpression of CXCR4 expression in prostate cancer cells by CXCL12 increases endothelial adhesion and transendothelial migration by regulating MEK/ERK signaling pathway-dependent NF-kappaB activation [93].Taken together, SDF-1 has a substantial role in angiogenesis and invasiveness of prostate cancer metastasis.

Prostaglandin E2 (PGE2)

Prostaglandin E2 is a predominant mediator of inflammatory diseases like rheumatoid arthritis and osteoarthritis [94]. Nonsteroidal anti-inflammatory medications (NSAIDs) and selective cyclooxygenase-2 (COX-2) inhibitors have an ability decreasing PGE2 production by diminishing the inflammation [95]. According to available literature, the tumorogenesis and progression of prostate cancer have been closely associated with PGE2 [96]. Report suggested PGE2 upregulated the mRNA and protein expression levels of MMP2, MMP9, RANKL and RUNX2 [97]. Metformin treatment suppressed inflammatory infiltration by downregulating PGE2 and COX2 in prostate cancer cells[98]. This suggested metformin could be used as anti-metastasis therapy by repressing the levels of COX2, PGE2 and phos phorylated STAT3 [99]. The study provides that metastasis of prostate cancer to bone is related to upregulated PGE2 produced by tumor-host stromal tissue and its receptor EP4 is most abundantly expressed subtype among EP receptors. Report suggested inhibition of PGE2-EP4 signaling hindered bone destruction by suppressing RANKL expression required for PC-3 osteoblast interaction, and may result in osteolysis [100].

Platelet-derived growth factors (PDGFs)

Platelet-derived growth factors are known as serum growth factors for fibroblasts, smooth muscle cells, and glial cells[101]. PDGFs play a significant role in angiogenesis by creating a group of growth factors. PDGF receptor alpha is a tyrosine-kinase (also known as PDGFRA and CD140a) acts as a cell-surface receptor for PDGF-A, PDGF-B, PDGF-C and PDGF-D [102]. PDGFR-A plays role in the regulation of cell proliferation, recruitment of mesenchymal cells and normal skeleton development [103]. Overexpression of PDGF-D has been associated with regulation of migration, invasion, proliferation, apoptosis and metastasis in numerous cancer cells including pancreatic, breast and prostate cancer [104]. Activation of nuclear factor-kappa B and Bcl-2 overexpression in PDGF-D was associated with increased aggressiveness of PC-3 cells. This data suggests PDGF-D could be a novel therapeutic target for the prevention and/or treatment of prostate cancer [105]. Report suggested that interruption of the PDGF-Mcl-1 signal induced apoptosis in metastatic prostate cancer cells by pharmacological inhibitor AG-17 [106]. Synthetic peptide of amino acids 31–45 (PCK3145) can reduce prostate tumor growth in vivo by inhibiting the PDGF-induced phosphorylation of PDGFR in smooth muscle cells. Investigation of the antiangiogenic properties of this peptide could be eminently favorable for patients with advanced prostate cancer metastasis [107]. PDGF has a significant role in bone metastasis of prostate cancer cells by regulating Akt/PKB survival pathway compared to non-metastatic cells. Overexpression of alpha-PDGFR expression is associated with the metastasis of prostate cancer to the skeleton [108]. It has been reported that, phosphorylation of EGF-R and PDGF-R in PC-3MM2 prostate cancer cells have been linked with advanced prostatecancer growth. Inhibition of EGF-R and PDGF-R by paclitaxel showed reduced lymph node metastasis and apoptosis of tumor stromal cells [109].

Summary and Conclusions

The involvement of growth factors in the development of prostate cancer metastasis has been a topic of debate for decades. In this review we aimed to provide insight by gathered and available data from the published literature. In a nutshell, we found that many of the growth factors significantly impact the metastasis of prostate cancer. Each and every step involved in metastasis beginning from loss of cell adhesion of tumor cells to tumor growth and angiogenesis is influenced by the presence of growth factors. The disruption of TGF-β signaling promotes tumor metastasis. IGF-1 plays a crucial role in initiating the metastasis while EGF family is involved in growth and invasion at the metastatic site. FGF helps in overall tumor progression. VEGF plays a key role in establishing angiogenn of TGF-β signaling promotes tumor metastasis. IGF-1 plays a crucial role in initiating the metastasis while EGF family is involved in growth and invasion at the metastatic site. FGF helps in overall tumor progression. VEGF plays a key role in establishing angiogenesis and thus facilitates tumor survival. In addition, preoperative plasma levels of HGF act as an independent predictor of prostate cancer metastasis to lymph nodes. Potential role of growth factors are as an aid in causing the metastasis of prostate cancer. Thus, an extensive analysis of growth factors may be the key to unlocking a significant number of new potential diagnostic and therapeutic targets. The implications of this review may be far-reaching, highlighting many growth factors that could become candidate targets for future drug or biomarker development. Additionally, many of these growth factors are relevant to other diseases occurring in other organs of the body; further studying prostate cancer metastasis as a platform could dramatically alter our outstanding of not just these but also other diseases.