Platelet-derived growth factor C induces liver fibrosis, steatosis, and hepatocellular carcinoma

Abstract

Members of the platelet-derived growth factor (PDGF) ligand family are known to play important roles in wound healing and fibrotic disease. We show that both transient and stable expression of PDGF-C results in the development of liver fibrosis consisting of the deposition of collagen in a pericellular and perivenular pattern that resembles human alcoholic and nonalcoholic fatty liver disease. Fibrosis in PDGF-C transgenic mice, as demonstrated by staining and hydroxyproline content, is preceded by activation and proliferation of hepatic stellate cells, as shown by collagen, ␣-smooth muscle actin and glial fibrillary acidic protein staining and between 8 and 12 months of age is followed by the development of liver adenomas and hepatocellular carcinomas. The hepatic expression of a number of known profibrotic genes, including type ␤1 TGF, PDGF receptors ␣ and ␤, and tissue inhibitors of matrix metalloproteinases-1 and -2, increased by 4 weeks of age. Increased PDGF receptor ␣ and ␤ protein levels were associated with activation of extracellular regulated kinase-1 and -2 and protein kinase B. At 9 months of age, PDGF-C transgenic mice had enlarged livers associated with increased fibrosis, steatosis, cell dysplasia, and hepatocellular carcinomas. These studies indicate that hepatic expression of PDGF-C induces a number of profibrotic pathways, suggesting that this growth factor may act as an initiator of fibrosis. Moreover, PDGF-C transgenic mice represent a unique model for the study of hepatic fibrosis progressing to tumorigenesis.fibrogenesis ͉ cancer ͉ hepatic stellate cells

Targeting Liver Fibrosis

“…Genetic models have great value to confirm factors and mechanisms that drive fibrogenesis or fibrolysis in vivo, even more because the models have been refined with the use of tissue-and cell-specific, or conditional transgenes or deletions. An example are transgenic mice with constitutive overexpression of PDGF-C, 41 or with conditional overexpression of TGF-␤ 42 or PDGF-B. 43 However, these models need further refinement because expression of the profibrogenic factors is typically driven by way of the albumin promoter in hepatocytes, whereas physiologically they are mainly produced by inflammatory cells and activated HSC.…”

Rationale for the development of IMC‐3G3, a fully human immunoglobulin G subclass 1 monoclonal antibody targeting the platelet‐derived growth factor receptor α

“…2). [44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60] Several types of cancers, particularly those derived from the ovary, prostate, breast, lung, brain, skin, and bone, express PDGFRa on the malignant cells themselves (Table 1). 22 In 1 experiment in which a human tumor array was probed with a cross-reactive polyclonal rabbit antibody to PDGFRa, PDGFRa expression was noted in approximately 95% of osteosarcomas and chondrosarcomas, in 77% of prostate cancers, in 52% of ovarian cancers, in 65% of breast cancers, and in 51% of lung cancers (N. Loizos, ImClone Systems, unpublished results).…”

“…59 Investigations in multiple cancer types have highlighted the relevance of both PDGF-activated tumor and supporting stromal cells in facilitating cancer growth and metastasis. [44][45][46][47][48][49][50][51]55,57,60 In some cases, specific autocrine or paracrine mechanisms that contribute to malignant progression have been suggested. In 1 experiment, NIH 3T3 cells were transformed when PDGF-A or PDGF-B gene expression was induced using a transfected promoter.…”

“…PDGFs can influence cancer growth and malignant angiogenesis through several mechanisms, including the activation of PDGFRa expressed on cancer cells, stromal fibroblasts, and vascular endothelial cells and by PDGF-induced production of vascular endothelial growth factor (VEGF) by stromal cells. [45][46][47][48][49][50][51][52][53][54][55]57,60 The asterisk indicates that Table 1 required for the development of malignant stroma, 46 a separate study indicated that the induction of PDGF-CC expression in melanoma cells led to accelerated tumor growth through the activation of PDGFRa. 47 In the latter study, the exclusive expression of PDGFRa on cancerassociated stromal fibroblasts illuminated a paracrine mechanism of stromal-regulated melanoma tumor growth.…”

“…47 In the latter study, the exclusive expression of PDGFRa on cancerassociated stromal fibroblasts illuminated a paracrine mechanism of stromal-regulated melanoma tumor growth. It also has been demonstrated that PDGF/ PDGFRa-associated autocrine or paracrine mechanisms that involve tumor and stroma similarly play important roles in the growth of hepatocellular cancers 48,49 and lung cancers, 51 in facilitating bone metastasis in prostate cancers, 60 and in the metastatic spread of lung and breast cancers. 45,57 It also has been established that an intact PDGF/ PDGFRa axis is required for vascular endothelial growth factor (VEGF) production by tumor stroma and for the regulation of malignant angiogenesis in tumors that are resistant to antiangiogenic treatment.…”