Diabetes mellitus is associated with liver metastasis of colorectal cancer through production of biglycan-rich cancer stroma
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Rina Fujiwara-Tani1, Takamitsu Sasaki1, Kiyomu Fujii1, Yi Luo1,2, Takuya Mori1, Shingo Kishi1, Shiori Mori1, Sayako Matsushima-Otsuka1, Yukiko Nishiguchi1, Kei Goto1, Isao Kawahara1, Masuo Kondoh3, Masayuki Sho4 and Hiroki Kuniyasu1
1 Department of Molecular Pathology, Nara Medical University, Kashihara, Nara 634-8521, Japan
2 Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu Province 226001, China
3 Drug Innovation Center, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka 565-0871, Japan
4 Department of Surgery, Nara Medical University, Kashihara, Nara 634-8522, Japan
Keywords: diabetes; liver metastasis; colorectal cancer; biglycan; mesenchymal stem cell
Received: May 27, 2020 Accepted: June 20, 2020 Published: August 04, 2020
High morbidity and mortality of cancer, especially colorectal cancer (CRC), in diabetic patients have been reported. In this study, we investigated the relationship between the presence of diabetes mellitus (blood hemoglobin A1C was 6.5% or higher at the time of diagnosis of CRC) and the progression and liver metastasis of CRC. Histopathological findings in the primary lesions, which were preferential to diabetes-complicated CRC (DM-CRC) and the liver metastasis, were also investigated. Of the 473 CRC patients who underwent curative surgical resection, 148 (31%) had diabetes. In DM-CRC cases, the stage was more advanced, with more cases in stage IV or postoperative disease recurrence. Histopathological findings correlated with liver metastasis in DM-CRC, including budding grade, perineural invasion, and myxomatous tumor stroma, and all were highly correlated with the stage. Additionally, myxomatous stroma showed the strongest correlation with liver metastasis in multivariate analysis. Myxomatous stroma in stage III cases correlated with liver recurrence. The myxomatous stroma was abundant in biglycan protein and contained numerous CD90-positive mesenchymal stem cells (MSCs). In human colon cancer cell line HT29, biglycan expression was induced by high sugar concentration, fatty acids, and insulin, and its contact co-culture with MSCs resulted in enhanced stemness and epithelial-mesenchymal transition phenotype. Thus, DM-CRC has higher malignant phenotypes compared to non-DM-CRC, and the involvement of diabetes-induced biglycan may act as a pathogenic factor.
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