Yashiro Masakazu, Kinoshita Haruhito, Tsujio Gen, Fukuoka Tatsunari, Yamamoto Yurie, Sera Tomohiro, Sugimoto Atsushi, Nishimura Sadaaki, Kushiyama Shuhei, Togano Shingo, Kuroda Kenji, Toyokawa Takahiro, Ohira Masaichi
Molecular Oncology and Therapeutics, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.
Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.
Oncol Lett. 2021 Jan;21(1):38. doi: 10.3892/ol.2020.12299. Epub 2020 Nov 12.
Stromal cell-derived factor 1α (SDF1α) and its receptor C-X-C chemokine receptor type 4 (CXCR4) have been reported to form an important chemokine signaling pathway. Our previous study reported that SDF1α from tumor stromal cells may stimulate the proliferation of gastric cancer (GC) cells through the CXCR4 axis in a hypoxic microenvironment. However, a limited number of studies have addressed the clinicopathological significance of the expression of SDF1α and CXCR4 in GC, particularly at hypoxic regions. Immunohistochemistry was used to investigate the expression levels of SDF1α, CXCR4 and the hypoxic marker carbonic anhydrase 9 (CA9) in 185 patients with stage II and III GC. The results demonstrated that CA9 was expressed on cancer and stromal cells in hypoxic lesions, CXCR4 was mainly expressed in cancer cells, and SDFα was mainly expressed in stromal cells. CXCR4 expression in cancer cells and SDFα expression in stromal cells were associated with the hypoxic regions with CA9 expression. The CA9 and CXCR4 expression in the cancer cells, and the SDF1α expression in the stromal cells (CA9/CXCR4/SDF1α) was significantly associated with macroscopic type 4 tumor (P=0.012) and the pattern of tumor infiltration into the surrounding tissue (P<0.001). The prognosis of the all CA9/CXCR4/SDF1α-positive patients was significantly poorer compared with that of patients with CA9-, CXCR4- or SDF1α-negative GC at Stage III (P=0.041). These results indicated that hypoxia may upregulate SDFα production in stromal cells and CXCR4 expression in cancer cells. The SDF1α/CXCR4 axis may serve an important role in the progression of GC.
据报道，基质细胞衍生因子1α（SDF1α）及其受体C-X-C趋化因子受体4（CXCR4）可形成一条重要的趋化因子信号通路。我们之前的研究报道，肿瘤基质细胞产生的SDF1α可能在缺氧微环境中通过CXCR4轴刺激胃癌（GC）细胞增殖。然而，针对SDF1α和CXCR4在GC中表达的临床病理意义的研究较少，尤其是在缺氧区域。采用免疫组织化学方法研究185例II期和III期GC患者中SDF1α、CXCR4和缺氧标志物碳酸酐酶9（CA9）的表达水平。结果表明，CA9在缺氧病变的癌细胞和基质细胞中表达，CXCR4主要在癌细胞中表达，而SDFα主要在基质细胞中表达。癌细胞中的CXCR4表达和基质细胞中的SDFα表达与CA9表达的缺氧区域相关。癌细胞中的CA9和CXCR4表达以及基质细胞中的SDF1α表达（CA9/CXCR4/SDF1α）与4型宏观肿瘤（P=0.012）以及肿瘤浸润周围组织的模式显著相关（P<0.001）。与III期CA9、CXCR4或SDF1α阴性的GC患者相比，所有CA9/CXCR4/SDF1α阳性患者的预后明显更差（P=0.041）。这些结果表明，缺氧可能上调基质细胞中SDFα的产生以及癌细胞中CXCR4的表达。SDF1α/CXCR4轴可能在GC进展中起重要作用。
