Paracrine signaling by platelet-derived growth factor-CC promotes tumor growth by recruitment of cancer-associated fibroblasts.
Paracrine signaling by platelet-derived growth factor-CC promotes tumor growth by recruitment of cancer-associated fibroblasts.
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DOI：
10.1158/0008-5472.can-08-2724
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发表时间：
2009-01-01
期刊：
影响因子：
11.2
通讯作者：
Pietras K
中科院分区：
文献类型：
--
作者：
Anderberg C;Li H;Fredriksson L;Andrae J;Betsholtz C;Li X;Eriksson U;Pietras K
癌症是恶性细胞和间质细胞协同作用的结果。微环境中的细胞类型被肿瘤征召来分泌一系列促进生长的信号，从而支持肿瘤的启动和进展。血小板衍生生长因子(PDGFs)通过一系列未知的分子效应分子支持肿瘤间质的形成。虽然PDGF-CC在一系列组织中诱导成纤维细胞的反应性和纤维化，但对PDGF-CC在形成肿瘤-间质相互作用中的作用知之甚少。在此，我们提出了恶性黑色素瘤中涉及PDGF-CC和PDGFR-α的旁分泌信号网络的证据。在小鼠模型中，PDGF-C的表达通过募集和激活不同的癌症相关成纤维细胞来加速肿瘤的生长。为了寻找肿瘤相关成纤维细胞提供的支持因子的分子同一性，我们利用抗体阵列和体内联合注射模型来确定骨桥蛋白是PDGF-CC促进肿瘤生长的效应因子。总之，我们通过PDGF-CC建立旁分泌信号作为减少恶性黑色素瘤间质支持的潜在药物靶点。
Cancer results from the concerted performance of malignant cells and stromal cells. Cell types populating the microenvironment are enlisted by the tumor to secrete a host of growth-promoting cues, thus upholding tumor initiation and progression. Platelet-Derived Growth Factors (PDGFs) support the formation of a prominent tumor stromal compartment by as of yet unidentified molecular effectors. While PDGF-CC induces fibroblast reactivity and fibrosis in a range of tissues, little is known about the function of PDGF-CC in shaping the tumor-stroma interplay. Herein, we present evidence for a paracrine signaling network involving PDGF-CC and PDGFR-α in malignant melanoma. Expression of PDGF-C in a mouse model accelerated tumor growth through recruitment and activation of different subsets of cancer-associated fibroblasts. In seeking the molecular identity of the supporting factors provided by cancer-associated fibroblasts we made use of antibody arrays and an in vivo co-injection model to identify osteopontin as the effector of the augmented tumor growth induced by PDGF-CC. In conclusion, we establish paracrine signaling by PDGF-CC as a potential drug target to reduce stromal support in malignant melanoma.