Local and systemic protumorigenic effects of cancer-associated fibroblast-derived GDF15.
The tumor stroma is vital to tumor development, progression, and metastasis. Cancer-associated fibroblasts (CAF) are among the abundant cell types in the tumor stroma, but the range of their contributions to cancer pathogenicity has yet to be fully understood. Here, we report a critical role for upregulation of the TGFβ/BMP family member GDF15 (MIC-1) in tumor stroma. GDF15 was found upregulated in situ and in primary cultures of CAF from prostate cancer. Ectopic expression of GDF15 in fibroblasts produced prominent paracrine effects on prostate cancer cell migration, invasion, and tumor growth. Notably, GDF15-expressing fibroblasts exerted systemic in vivo effects on the outgrowth of distant and otherwise indolent prostate cancer cells. Our findings identify tumor stromal cells as a novel source of GDF15 in human prostate cancer and illustrate a systemic mechanism of cancer progression driven by the tumor microenvironment. Further, they provide a functional basis to understand GDF15 as a biomarker of poor prognosis and a candidate therapeutic target in prostate cancer.
Authors' Affiliations: Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale"-IRCCS, Naples, Italy;
Francesca
F
Bruzzese
Department of Medical Biosciences, Pathology, Umeå University, Umeå;
Christina
C
Hägglöf
Authors' Affiliations: Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale"-IRCCS, Naples, Italy;
Alessandra
A
Leone
Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
Elin
E
Sjöberg
Authors' Affiliations: Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale"-IRCCS, Naples, Italy;
Maria Serena
MS
Roca
Department of Immunology, Genetics, and Pathology, Uppsala University, Uppsala; and.
Sara
S
Kiflemariam
Department of Immunology, Genetics, and Pathology, Uppsala University, Uppsala; and.
Tobias
T
Sjöblom
Department of Medical Biosciences, Pathology, Umeå University, Umeå;
Peter
P
Hammarsten
Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
Lars
L
Egevad
Department of Medical Biosciences, Pathology, Umeå University, Umeå;
Anders
A
Bergh
Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
Arne
A
Ostman
Authors' Affiliations: Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale"-IRCCS, Naples, Italy;
Alfredo
A
Budillon
Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden martin.augsten@ki.se.
Martin
M
Augsten
D016475:3T3 Cells; D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D055436:Growth Differentiation Factor 15 / Q000096:biosynthesis / Q000235:genetics*; D064593:Heterografts / Q000254:growth & development; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009361:Neoplasm Invasiveness / Q000473:pathology; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms / Q000473:pathology*; D059016:Tumor Microenvironment; D015854:Up-Regulation
D014408:Biomarkers, Tumor; C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15