Int J Clin Exp Med 2017;10(7):9918-9929 www.ijcem.com /ISSN:1940-5901/IJCEM0055300 Review Article PDGF signaling in cancer progression Feng Huang1, Dong Wang2, Yongliang Yao1, Mei Wang3 1Department of Clinical Laboratory, The First People’s Hospital of Kunshan, Affiliated to Jiangsu University, Suzhou, Jiangsu Province, China; 2Department of Burn and Plastic Surgery, Affiliated Hospital of Nantong Univer- sity, Nantong, China; 3School of Medicine, Jiangsu University, Zhenjiang, Jiangsu Province, China Received April 12, 2017; Accepted June 7, 2017; Epub July 15, 2017; Published July 30, 2017 Abstract: Platelet-derived growth factor (PDGF) is a pro-angiogenic factor that was isolated from human platelets. PDGF family is comprised of four different polypeptide chains encoded by different genes, which have been iden- tified: PDGF-A, PDGF-B, and recently discovered PDGF-C and PDGF-D. PDGF is a variety of strong mesenchymal cell mitogenic agents and growth chemokines. PDGF, acting as a vascular endothelial growth factor, is closely as- sociated with tumor development. PDGF signaling pathway has been extensively studied and well characterized because PDGF can regulate many cellular processes, including cell proliferation, migration, invasion, angiogenesis and metastasis. According to the available data, PDGF plays an important role in the development of breast cancer, stomach cancer, gastric cancer, prostate cancer, lung cancer, colon cancer, and other cancers. Effects of PDGF on cancer are complex and diverse, and further analysis is needed to confirm the predictive and therapeutic values of PDGF and its receptor. This article reviews the recent progress of PDGF in tumor progression. Keywords: Platelet-derived growth factor, signal pathway, proliferation, migration, invasion, angiogenesis, metas- tasis, tumor progression Introduction PDGF domain, which can induce the phosphory- lation of β-PDGF receptor and stimulate LNCaP Platelet-derived growth factor (PDGF) is a pro- cell proliferation in an autocrine manner. angiogenic factor that was isolated from human Additionally, LNCaP-PDGFD-conditioned medi- platelets [1-3]. PDGFs are a variety of strong um induces migration of the prostate fibroblast mesenchymal cell mitogenic agents and growth cell line 1532-FTX, indicating LNCaP-processed chemokines; they are also important modifiers PDGFD acts in a paracrine manner as well. The for the normal and pathological vascular devel- PDGF signaling pathway combines with a vari- opment [4-6]. PDGF, acting as vascular endo- ety of substrate protein signaling molecules, thelial growth factor, plays a pivotal role in the including SRC tyrosine kinase subfamily, development and progression of human malig- phospholipase C (PLC-γ), phosphatidylinositol nancies. The latest findings show that PDGFs 3-kinase (PI3-K), GTPase activation protein regulate tumor growth and metastasis by tar- (RAS-gap), growth factor binding protein (Grb2), geting malignant cells, vascular cells, and stro- tyrosine specific phosphatase (SYP), Src homol- mal cells [7-10]. ogy and cross-linked protein (SHC) and adapta- PDGF and cancer cells tion (Crk) protein, and non-receptor tyrosine kinase family (SRC) and so on, and forms a vari- Cancer cell proliferation ety of signaling pathways, such as RAS-MAPK pathway, PI3-K pathway, the PLC pathway, and PDGF stimulates cancer cell proliferation STAT pathway [13]. These signal molecules through autocrine and paracrine manners, mediate cytoplasmic complex signaling net- since some cancer cells express the PDGF works, and play a role in cell membrane serine receptor and some do not. For example, Ustach threonine residues, resulting in a variety of et al. [11, 12] demonstrated that LNCaP cells gene regulation and protein phosphorylation, auto-activate latent PDGFD into the active thus promoting cancer cell growth and division PDGF signaling in cancer progression [14]. For example, PDGF has been proved to ing number of researchers believe that cancer promote the proliferation of human meningio- growth, metastasis, and invasion depend not mas and mesothelioma cell through PI3-K only on the tumor cells themselves, but also on pathway [15, 16]. Lu Y. demonstrated that the growth of tumor microenvironment, which hypoxia-induced PDGF-BB secretion by HCC supports cancer behavior. Studies have shown cells stimulates HSCs to accumulate and prolif- that PDGF-C in breast cancer activates the erate in the tumor stroma [17]. Whereas angio- receptor by binding to the receptor, and activa- genesis inhibitor sorafenib downregulates the tion of the receptor leads to tyrosine kinase expression of PDGF-BB and TGF-β1 in the HSCs pathway activation, which mediates fibroblast supernatant, and restrains the viability of the activation and is involved in the secretion of a HSCs, resulting in suppressed proliferation variety of cytokines and the formation of cellu- and invasion in HepG2 cells [18]. Meanwhile, lar microenvironment [26]. Activated fibro- Platelet-derived growth factor receptor (PDGFR) blasts, known as cancer-associated fibroblasts signaling participates in different processes in (CAFs), promote the formation of tumor metas- solid tumors, including autocrine stimulation of tasis and directional vessel by secreting SDF-1/ tumor cell growth, recruitment of tumor stroma CXCR4. CAFs also can promote tumor growth fibroblasts, and stimulation of tumor angio- and metastasis by secreting other factors such genesis [19]. Moreover, malignant melanoma as hepatocyte growth factor (HGF), epidermal upregulates hyaluronan synthesis in fibroblasts growth factor (EGF), basic fibroblast growth fac- by releasing PDGF-AA and PDGF-CC, which in tor (b FGF), and insulin-like growth factor (IGF). turn stimulates the malignant melanoma cell PDGF-DD secreted by gastric cancer-derived proliferation in a paracrine manner [20]. PDGF mesenchymal stem cells (GC-MSCs) is capable also increases proliferation of Luminal breast of promoting gastric cancer cell proliferation cancer cells in the absence of estrogens [21]. and migration in vitro and in vivo. Jieqiong Liu et In conclusion, PDGF induces proliferation and al. [27] reported that overexpression of PDGF-D migration of tumor cells and inhibits apoptosis promoted tumor growth and lymph node [21]. metastasis through increased proliferation, decreased apoptosis, and induction of CXCR4 Cancer cells metastasis expression [28]. A study reports a mechanism of the interaction between perivascular cells Cancer cell metastasis begins with detachment and tumor-associated macrophages (TAMs) of metastatic cells from the primary tumor, trav- that promotes metastasis through the IL-33- eling of the cells to different sites through ST2-dependent pathway in xenograft mouse blood/lymphatic vessels, settlement and models of cancer. While PDGF-BB upregulates growth of the cells at a distal site [22]. During IL-33 gene though stimulating the activation of the process, metastatic cells go through pericytes SOX7 transcription factor. Gain- and detachment, migration, invasion, and adhesion loss-of-function experiments validated that [22]. For tumor metastasis, cardiovascular gen- IL-33 promotes metastasis through recruit- eration is required, which provides oxygen and ment of TAMs. Pharmacological inhibition of nutrients for tumor growth and metastasis. the IL-33-ST2 signaling by a soluble ST2 PDGF can promote connective tissue to pro- significantly inhibits TAMs and metastasis [29]. duce extracellular matrix proteins, which direct- Genetic deletion of host IL-33 in mice blocks ly or indirectly induces tumor angiogenesis, PDGF-BB-induced TAM recruitment and metas- significantly affecting tumor metastasis. PDGF- tasis [29]. Yasuhiko Kitadai discovered that D-overexpressing tumors express higher levels expression and phosphorylation of PDGF-Rb by of MMP-9 and PDGFD to induce renal cancer stromal cells and pericytes was higher in ortho- cells proliferation and migration, thus providing topic tumors than in ectopic tumors and, there- a molecular mechanism for the higher inci- fore, was associated with the metastatic poten- dence of lung metastasis and pericyte cover- tial of the neoplasms [30]. PDGFs may also age observed in PDGF-D-overexpressing tu- have a role in determining the preferential mors [23, 24]. PDGFD plays an important role organ of metastatization. Indeed, PDGFs in breast tumor aggressiveness and this pro- released by the tumor cells are potent che- cess is mechanistically linked with the activa- moattractants and mitogens for host mesen- tion of Notch and NF-κB signaling [25]. A grow- chymal cells and could mediate the interac- 9919 Int J Clin Exp Med 2017;10(7):9918-9929 PDGF signaling in cancer progression tions between cancer cells and the host mote the cell recruitment in peripheral blood environment of the preferred metastatic site vessel wall and increase the stability of the [31]. PDGF plays an important role in epithelial structure [38]. The recruitment of peripheral mesenchymal transition. For example, it has blood cells increased blood vessel coverage been recently demonstrated that autocrine which may lead to the resistance to anti-angio- PDGF signaling maintains EMT and promotes genic drugs. In the study of Zhao Z et al., PDGFD metastatization in mouse mammary carcinoma is one of the key candidate genes which may and tumor dissemination [32]. PDGF promotes influence chemo sensitivity of glioblastoma EMT via activation of STAT3 or PI3K pathway (GBM) to Semustine (Me-CCNU) [39]. and PDGF-D over-expression was positively