PDGF/PDGFR Effects in Osteosarcoma and the “Add-On” Strategy
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Xu et al. Clin Sarcoma Res (2018) 8:15 https://doi.org/10.1186/s13569-018-0102-1 Clinical Sarcoma Research REVIEW Open Access PDGF/PDGFR efects in osteosarcoma and the “add‑on” strategy Jie Xu, Lu Xie and Wei Guo* Abstract New treatment options for advanced osteosarcoma have remained limited. The platelet-derived growth factor (PDGF)/platelet-derived growth factor receptor (PDGFR) pathway plays an important role in the development and metastasis of osteosarcoma, via either direct autocrine stimulation of tumor cells, or paracrine stimulation on tumor stromal cells. It promotes angiogenesis to overcome hypoxia in the tumor microenvironment, and modulates tumor interstitial fuid pressure to control the infux and efux of other agents. Targeting the PDGF/PDGFR pathway is a promising therapeutic method to overcome drug resistance and improve patients’ outcome in osteosarcoma. Further evidence is needed to defne the detailed mechanism. Results from clinical trials using PDGF/PDGFR inhibitor as a single agent were disappointing, both in osteosarcoma and soft tissue sarcoma. However, when combined with other agents, named as “add-on” strategy, a synergistic antitumor efect has been confrmed in soft tissue sarcoma, and should be attempted in osteosarcoma. Keywords: PDGF, PDGFR, Osteosarcoma, Add-on therapy Background tumor growth, invasiveness, drug resistance, and poor Osteosarcoma is the most common primary bone malig- clinical outcomes [9]. Te PDGF pathway is also a key nancy in adolescents and young adults, with an incidence signal for tumor stromal cells recruitment such as can- rate of 4.4 cases per 1 million each year in people aged cer-associated fbroblasts [10], which play an important 0–24 years [1]. Current multidisciplinary treatments have role in the maintenance of tumor microenvironment. Te led to a dramatic improvement in prognosis for patients exact mechanism leading to the development and metas- with localized osteosarcoma; long-term survival rates of tasis of osteosarcoma is not fully understood. Te PDGF less than 20% improved to 65–70% [2]. Unfortunately, receptor does not appear to be as central to prolifera- with metastatic disease, the rate of long-term survival is tion for osteosarcoma cultures as Bcr/Abl is for chronic greatly reduced to 20–30% [3, 4]. Although several clini- myelogenous leukemia. Although PDGF is known to cal trials have been conducted, and new drugs such as stimulate proliferation and diferentiation of osteoblasts sorafenib and everolimus have been tested in metastatic and osteoclasts [11], its role in osteosarcoma, specifcally osteosarcoma, the overall outcome has not signifcantly PDGF ligands and their receptors, is poorly understood. improved over the past few decades [5–7]. Te event-free Whether treatment with PDGF/PDGF receptor antago- survival for refractory or relapsed osteosarcoma is as low nists will be benefcial for osteosarcoma is the subject as 12% at 4 months [7]. of ongoing studies. In this article, we summarize the Platelet-derived growth factors (PDGFs) and their preclinical and clinical studies of the PDGF pathway in receptors (PDGFRs) are major players in oncogenesis and osteosarcoma, and discuss the mechanism and future drug resistance, and are attractive oncologic targets in directions. cancer [8]. PDGFs/PDGFRs are frequently expressed in various tumors, and their expression levels correlate with Overview of PDGF signaling Activation and function of PDGF/PDGFR pathway The platelet-derived growth factor (PDGF) signaling *Correspondence: [email protected] Peking University People’s Hospital, Beijing 100044, China network consists of four ligands, PDGF-A, PDGF-B, © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Xu et al. Clin Sarcoma Res (2018) 8:15 Page 2 of 9 PDGF-C, and PDGF-D, and two receptors, PDGFR-α PDGF/PDGFR pathway in tumor development and PDGFR-β. All PDGFs function as disulfide-linked and metastasis homodimers, but only PDGF-A and -B can form func- A complex interplay between cancer cells, endothelial tional heterodimers. Before binding to the protein cells, and other stromal cells occurs in tumor angiogen- tyrosine kinase receptors PDGFR-α and PDGFR-β, the esis. Te PDGF/PDGFR pathway plays an important four PDGF ligands are inactive in their monomeric role in the development and metastasis of tumors in at forms. The receptor isoforms dimerize upon bind- least three diferent ways: (1) direct autocrine stimu- ing, leading to three possible receptor combinations, lation of tumor cells [17]; (2) paracrine stimulation of namely -AA, -BB, and -AB, causing the subsequent tumor stromal cells [12] and promotion of angiogenesis activation of kinase. Kinase activation is visualized as to overcome hypoxia in the tumor microenvironment tyrosine phosphorylation of the receptor molecules, [18]; (3) modulation of tumor interstitial fuid pressure which occurs between the dimerized receptor mole- (IFP) to control the infux and efux of agents [19]. cules (transphosphorylation). The receptor molecules Te mode of action of PDGF and PDGFR involve- then undergo conformational changes that allow a ment in tumor development and progression is mainly basal kinase activity to phosphorylate a critical tyros- through direct autocrine stimulation of tumor cell ine residue, thereby “unlocking” the kinase, leading to growth and cell autonomy, whereas in normal tis- full enzymatic activity directed toward other tyrosine sues paracrine stimulation is predominant [20]. Direct residues in the receptor molecules, as well as other blockade of autocrine stimulation using inhibitors of substrates for the kinase [12, 13]. PDGFR in cell lines and xenograft models show posi- More than 10 diferent molecules bind selectively to tive results in tumors such as lung cancer [21], hepatic phosphorylated residues in the PDGF receptors, includ- cancer [22], gastrointestinal stromal tumor (GIST) [23], ing the Src family, SHP-2 tyrosine phosphatase, phospho- dermatofbrosarcoma protuberans [24], and osteosar- lipase C-γ (PLC-γ), and the GTPase activating protein coma, which expressed PDGFR-α on the cell surface (GAP) for Ras. Furthermore, the receptors bind and [25]. Te levels of phosphorylation of both PDGFRs activate signal transducers and activators of transcrip- and the downstream signaling proteins such as pro- tion (STATs). Finally, some of the receptors binding mol- tein kinase B (AKT) and extracellular regulated kinase ecules lack intrinsic enzymatic activities, but can form (ERK) are downregulated by PDGFR antibodies or complexes with other signaling molecules. For example, small molecular tyrosine kinase inhibitors (TKIs) [25]. the regulatory subunit p85 of the PI3K forms a complex In addition to direct autocrine stimulation, the with the p110 catalytic subunit, and Grb2 activates Ras PDGF/PDGFR pathway exerts paracrine stimulation and the Erk MAP-kinase pathway by binding with SOS1. on tumor stromal cells. PDGF promotes the formation In addition, the PDGF receptors bind other adaptors of a rich stromal compartment, characterized by depo- (e.g., Shc, Nck, Crk, and GAB) and mediate interactions sition of extracellular matrix components and blood with numerous diferent downstream signaling mole- vessel formation [26]. Experimental models showed cules [14, 15]. Te activation of these signaling pathways that VEGF-null cells require PDGFR to recruit fbro- leads to cell survival, proliferation, angiogenesis, and cell blasts in tumor stroma [27]. Cancer-associated fbro- migration. blasts (CAFs), which secrete several active factors to PDGFs and PDGFRs are expressed by a large variety stimulate angiogenesis and tumor invasion, constitute a of normal human tissues and organs. PDGFs are major functionally important component of tumor stroma in mitogens for many cell types of mesenchymal or neuro- many types of cancer [28]. ectodermal in origin. PDGFs have chemo-attractant Clinical data indicate that carcinomas with desmo- properties and are involved in erythropoiesis, wound plastic stroma, consisting of fbroblast cells and extra- healing, bone formation, and angiogenesis. Much evi- cellular matrix, are associated with a poor prognosis dence suggests involvement in the normal development [29]. An experimental model of glioma revealed that of important organs such as kidney, brain, and cardio- PDGF-B enhances angiogenesis by stimulating VEGF vascular and respiratory systems [16]. During normal expression in tumor-associated endothelial cells and development, cell proliferation signifcantly increases as by recruiting pericytes [30]. Several other preclinical a consequence of PDGF overexpression and decreases in models demonstrated that using antibodies or TKIs PDGF null mutants. to disrupt the paracrine signaling with PDGFR can Xu et al. Clin Sarcoma Res (2018) 8:15 Page 3 of 9 signifcantly reduce tumor growth by inhibiting tumor of PDGF-AA expression were associated with a signif- cell growth, recruitment of fbroblasts, and angiogene- cantly lower 5-year disease-free