Bone marrow derived “fibrocytes” contribute to tumor proliferation and fibrosis in gastric cancer

• Published in: Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association 2015-04, Vol.18 (2), p.306-313
• Main Authors: Terai, Shiro, Fushida, Sachio, Tsukada, Tomoya, Kinoshita, Jun, Oyama, Katsunobu, Okamoto, Koichi, Makino, Isamu, Tajima, Hidehiro, Ninomiya, Itasu, Fujimura, Takashi, Harada, Shinichi, Ohta, Tetsuo
• Format: Article
• Language: English
• Subjects: Abdominal Surgery; Animals; Blotting, Western; Bone Marrow - metabolism; Bone Marrow - pathology; Cancer Research; Cell Movement; Cell Proliferation; Cells, Cultured; Chemokine CXCL12 - genetics; Chemokine CXCL12 - metabolism; Female; Fibroblasts - metabolism; Fibroblasts - pathology; Fibrosis - metabolism; Fibrosis - pathology; Gastric cancer; Gastroenterology; Humans; Immunoenzyme Techniques; Medicine; Medicine & Public Health; Mice; Mice, Inbred BALB C; Mice, Nude; Oncology; Original; Original Article; Real-Time Polymerase Chain Reaction; Receptors, CXCR4 - genetics; Receptors, CXCR4 - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Stomach Neoplasms - physiopathology; Surgical Oncology; Xenograft Model Antitumor Assays
• ISSN: 1436-3291; 1436-3305
• DOI: 10.1007/s10120-014-0380-0

Background Cancer-associated fibroblasts (CAFs) in the stroma are considered to play important roles for gastric cancer proliferation, invasion, and fibrosis, but the source of CAFs and their interaction with cancer cells in the microenvironment have not been fully determined. Here we elucidated the role of bone marrow-derived cells, fibrocytes, in development of gastric cancers, as represented by scirrhous gastric cancer. Materials and methods In co-culturing MKN45 gastric cancer cells and purified fibrocytes from healthy volunteers, migration and endothelial mesenchymal transition associated gene expression were evaluated using western blot analysis. Also, mouse xenograft models of MKN45 with or without fibrocytes were conducted to investigate their tumorigenicity and immunohistological differences of tumors. Results Co-culture of fibrocytes with MKN45 resulted in morphological changes from cobblestone-shape to spindle-shape and enhanced expression of α-SMA and collagen type I in fibrocytes, suggesting that co-culture with gastric cancer cells may have induced the differentiation of fibrocytes to myofibroblasts. Furthermore, enhanced expression of SDF-1 in MKN45 and CXCR4 in fibrocytes were also determined. Mouse xenograft models inoculated with MKN45 and fibrocytes revealed significantly larger tumors than those inoculated with MKN45 cells alone, and the stroma in co-inoculated tumors consisted of myofibroblasts and fibrosis. Mouse-derived cells expressing both CD45 and type I collagen were also observed in co-inoculated tumors. Conclusion Fibrocytes derived from bone marrow may migrate into the microenvironment of gastric cancer by SDF-1/CXCR4 system, and enhance the tumor proliferation and fibrosis as CAFs.