PO.TB10.16 · 肿瘤生物学
阻断弥漫型胃癌细胞与癌相关成纤维细胞之间异细胞黏附的化合物的鉴定与表征
Identification and characterization of compounds that block heterocellular adhesion between diffuse-type gastric cancer cells and cancer-associated fibroblasts
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摘要 Abstract
中文摘要
癌细胞的表型深受肿瘤微环境中与肿瘤基质的相互作用的深刻影响。在基质成分中,癌相关成纤维细胞(CAFs)含量最丰富,在塑造肿瘤环境中发挥关键作用。CAFs通过分泌促肿瘤因子和重塑细胞外基质来促进癌症进展。除这些旁分泌效应外,近期研究强调了癌细胞与CAFs之间直接异细胞黏附在肿瘤进展中的关键作用。弥漫型胃癌(DGC)是胃癌中最具侵袭性的亚型,预后极差。DGC以快速浸润性生长和频繁的腹膜转移为特征,常伴有由CAFs广泛增殖所致的促结缔组织增生性基质。我们此前证实,与CAFs的直接相互作用对DGC细胞的侵袭和腹膜转移至关重要。为进一步阐明这种相互作用的生物学意义,我们建立了一个高通量筛选系统,以鉴定破坏DGC细胞与CAF黏附的分子。利用该筛选系统,我们成功获得了能够阻断这种异细胞黏附并在体内抑制DGC腹膜转移的单克隆抗体。在本研究中,我们旨在鉴定抑制DGC细胞与CAFs之间异细胞黏附的小分子化合物。对一个化学文库进行高通量筛选,鉴定出数个命中化合物。值得注意的是,其中一种化合物不仅抑制了DGC细胞与CAF的黏附,还抑制了DGC细胞的增殖。此外,该化合物在小鼠异种移植模型中显著减少了DGC的腹膜转移。这些发现表明,靶向癌细胞与CAFs之间的异细胞黏附是一种有前景的治疗策略,破坏这种相互作用的小分子可能成为新型抗癌药物。
查看英文原文 English abstract
The phenotypes of cancer cells are profoundly influenced by reciprocal interaction with the tumor stroma within the tumor microenvironment. Among stromal components, cancer-associated fibroblasts (CAFs) are the most abundant and play pivotal roles in shaping the tumor milieu. CAFs promote cancer progression through the secretion of pro-tumorigenic factors and remodeling of the extracellular matrix. In addition to these paracrine effects, recent studies have emphasized the critical role of direct heterocellular adhesion between cancer cells and CAFs in tumor progression. Diffuse-type gastric cancer (DGC) is the most aggressive subtype of gastric cancer with an extremely poor prognosis. DGC is characterized by rapid infiltrative growth and frequent peritoneal metastasis. DGC is commonly accompanied by desmoplastic stroma, which results from the extensive proliferation of CAFs. We previously demonstrated that direct interactions with CAFs are essential for the invasion and peritoneal metastasis of DGC cells. To further elucidate the biological significance of this interaction, we established a high-throughput screening system to identify molecules that disrupt DGC cell-CAF adhesion. Using this screening system, we successfully obtained monoclonal antibodies that block this heterocellular adhesion and suppress peritoneal metastasis of DGC in vivo. In the present study, we aimed to identify small-molecule compounds that inhibit heterocellular adhesion between DGC cells and CAFs. High-throughput screening of a chemical library led to the identification of several hit compounds. Notably, one compound not only inhibited DGC cell-CAF adhesion but also suppressed the proliferation of DGC cells. Furthermore, this compound markedly reduced peritoneal metastasis of DGC in a mouse xenograft model. These findings suggest that targeting the heterocellular adhesion between cancer cells and CAFs represents a promising therapeutic strategy, and that small molecules disrupting this interaction may serve as novel anti-cancer agents.
利益披露 Disclosure
H. Yamaguchi, None..
Y. Nagamura, None..
M. Miyazaki, None.