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Paracrine Signaling by Platelet-Derived Growth Factor-CC Promotes Tumor Growth by Recruitment of Cancer-Associated Fibroblasts

¹ Ludwig Institute for Cancer Research Ltd., Stockholm Branch, and ² Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden; and ³ National Eye Institute, NIH, Bethesda, Maryland

Requests for reprints: Kristian Pietras, Ludwig Institute for Cancer Research Ltd., Nobels Väg 3, Box 240, Stockholm, SE-171 77, Sweden. Phone: 46-8-524-822-46; Fax: 46-8-332-812; E-mail: Kristian.Pietras{at}LICR.KI.SE.

Key Words: Cancer-associated fibroblast • Malignant melanoma • Osteopontin • Platelet Derived Growth Factor

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 (PDGF) support the formation of a prominent tumor stromal compartment by as of yet unidentified molecular effectors. Whereas 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 PDGF receptor- in malignant melanoma. Expression of PDGFC 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 coinjection 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. [Cancer Res 2009;69(1):369–78]

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