Abstract 171: Adipose-derived mesenchymal stem cell (ADSC) has the differentiation capacity toward cancer associated fibroblast (CAF) and reproduce the morphology of the clinical tumor stroma
Authors: Inagaki Yuki , Oda Tatsuya , Kurokawa Tomohiro , Miyamoto Ryoichi , Kida Yasuyuki , Ohkohchi Nobuhiro 
Published: May 2015

[Objectives] Crosstalk between cancer cells and Cancer-Associated Fibroblast (CAF) plays a crucial role that comprises 3D organization of solid cancers. It seems general understanding that the main origin of CAF is circulating bone marrow derived Mesenchymal Stem Cell (BM-MSC), though locally pre-existing resident MSC of adipose tissue (AD-MSC) should partly contribute to CAF formation. The role of CAF and MSC to tumorigenesis remains controversial,since some studies reported cancer stimulating effect by externally added MSC or its potential differentiating into CAF, while others showed its suppressive effect. The capability of MSC's innate tropism for cancer, which enables us to apply it for the cellular delivery of anti-cancer molecules, has attracted much attention. One of the key issues should be whether externally added MSC would accepted as a member of cancer 3D organization, and would contribute to the cancer morphology. We tried to reveal whether AD-MSC, which is much convenient source as engineered MSC than BM-MSC, stimulates or inhibit tumor growth, and how MSC contribute to tumor stromal morphogenesis.

[Materials & Methods]

Experiment: To evaluate the growth advantage by adding MSC, and how MSC contribute to tumor stromal morphogenesis, two differently-originated ADSC cell lines transfected with GFP was mixed with human pancreatic-cancer cell line (Capan-1) at a rate of 3×106 /5×106 , and inoculated into the back subcutaneous resion of BALB/cAJcl-nu/nu mice. The tumor volume was calculated at Day4, Day7 and Day10 to assess the growth advantage of tumor mixed with ADSC. The mice was sacrificed at Day 10 and the histology of the resected tumor was evaluated with fluorescence microscopy and immunostaining procedure with anti-GFP antibody.

[Results]

Capan-1 formed significantly larger subcutaneous tumor by adding with both two AD-MSC cell lines(352mm3,265mm3) compared to control (70mm3) at Day10. In the tumor mixed with one ADSC cell line, cancer cells formed ductal stractures and contained fiber rich stroma with GFP positive fibroblasts among cancer ducts, mimicked the similar distribution to that in clinical solid cancer specimen. However, in the graft with the other ADSC cell line, cancer cells presented cord-like structures or deregulated cell proliferation, not formed ductal stractures. Though GFP positive cells could be observed, they thinly and rondamly distributed in the stroma.

[Discussion]

Both two AD-MSC plays promotive role in tumor growth, and one of which strongly contribute to the tumor stromal morphogenesis. Our AD-MSC could be regarded as a case which obviously differentiated into CAF, and would be a good candidate source for forecomming CAF therapy. Further studies revealing CAFs specific signature would helpful for providing stable AD-MSC source.

Citation Format: Yuki Inagaki, Tatsuya Oda, Tomohiro Kurokawa, Ryoichi Miyamoto, Yasuyuki Kida, Nobuhiro Ohkohchi. Adipose-derived mesenchymal stem cell (ADSC) has the differentiation capacity toward cancer associated fibroblast (CAF) and reproduce the morphology of the clinical tumor stroma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 171. doi:10.1158/1538-7445.AM2014-171