Stromal-derived IGF2 promotes colon cancer progression via paracrine and autocrine mechanisms

Autor: Daniela Unterleuthner, Markus Hengstschläger, D Lenhardt, Angelika Riedl, Martin Scherzer, Helmut Dolznig, Andreas Wernitznig, Alexandra Burian, Albin Rudisch, Michaela Schlederer, Stefanie Walter, Julia Schüler, Wolfgang Sommergruber, Nina Kramer, Lukas Kenner, Christine Unger, Mira Stadler
Rok vydání: 2016
Předmět:
0301 basic medicine
Cancer Research
medicine.medical_specialty
animal structures
Stromal cell
endocrine system diseases
Paracrine Communication
SMAD
Biology
Transfection
Receptor
IGF Type 1
03 medical and health sciences
Paracrine signalling
Mice
0302 clinical medicine
Growth factor receptor
Insulin-Like Growth Factor II
Mice
Inbred NOD
Internal medicine
Cell Line
Tumor
Genetics
medicine
Animals
Humans
Autocrine signalling
Molecular Biology
Insulin-like growth factor 1 receptor
Receptors
Somatomedin
Fibroblasts
HCT116 Cells
female genital diseases and pregnancy complications
Autocrine Communication
030104 developmental biology
Endocrinology
030220 oncology & carcinogenesis
Cancer research
Disease Progression
Heterografts
Female
Caco-2 Cells
Stromal Cells
Colorectal Neoplasms
Transforming growth factor
Signal Transduction
Zdroj: Oncogene. 36(38)
ISSN: 1476-5594
Popis: The insulin-like growth factor (IGF)2/IGF1 receptor (IGF1R) signaling axis has an important role in intestinal carcinogenesis and overexpression of IGF2 is an accepted risk factor for colorectal cancer (CRC) development. Genetic amplifications and loss of imprinting contribute to the upregulation of IGF2, but insufficiently explain the extent of IGF2 expression in a subset of patients. Here, we show that IGF2 was specifically induced in the tumor stroma of CRC and identified cancer-associated fibroblasts (CAFs) as the major source. Further, we provide functional evidence that stromal IGF2, via the paracrine IGF1R/insulin receptor axis, activated pro-survival AKT signaling in CRC cell lines. In addition to its effects on malignant cells, autocrine IGF2/IGF1R signaling in CAFs induced myofibroblast differentiation in terms of alpha-smooth muscle actin expression and contractility in floating collagen gels. This was further augmented in concert with transforming growth factor-β (TGFβ) signaling suggesting a cooperative mechanism. However, we demonstrated that IGF2 neither induced TGFβ/smooth muscle actin/mothers against decapentaplegic (SMAD) signaling nor synergized with TGFβ to hyperactivate this pathway in two dimensional and three dimensional cultures. IGF2-mediated physical matrix remodeling by CAFs, but not changes in extracellular matrix-modifying proteases or other secreted factors acting in a paracrine manner on/in cancer cells, facilitated subsequent tumor cell invasion in organotypic co-cultures. Consistently, colon cancer cells co-inoculated with CAFs expressing endogenous IGF2 in mouse xenograft models exhibited elevated invasiveness and dissemination capacity, as well as increased local tumor regrowth after primary tumor resection compared with conditions with IGF2-deficient CAFs. In line, expression of IGF2 correlated with elevated relapse rates and poor survival in CRC patients. In agreement with our results, high-level coexpression of IGF2 and TGFβ was predicting adverse outcome with higher accuracy than increased expression of the individual genes alone. Taken together, we demonstrate that stroma-induced IGF2 promotes colon cancer progression in a paracrine and autocrine manner and propose IGF2 as potential target for tumor stroma cotargeting strategies.
Databáze: OpenAIRE
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