SEMA3C 通过 Plexin B1 反式激活多种受体酪氨酸激酶促进肿瘤生长。

SEMA3C drives cancer growth by transactivating multiple receptor tyrosine kinases via Plexin B1.

机构信息

Vancouver Prostate Centre, Vancouver, BC, Canada.

Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.

出版信息

EMBO Mol Med. 2018 Feb;10(2):219-238. doi: 10.15252/emmm.201707689.

Growth factor receptor tyrosine kinase (RTK) pathway activation is a key mechanism for mediating cancer growth, survival, and treatment resistance. Cognate ligands play crucial roles in autocrine or paracrine stimulation of these RTK pathways. Here, we show SEMA3C drives activation of multiple RTKs including EGFR, ErbB2, and MET in a cognate ligand-independent manner via Plexin B1. SEMA3C expression levels increase in castration-resistant prostate cancer (CRPC), where it functions to promote cancer cell growth and resistance to androgen receptor pathway inhibition. SEMA3C inhibition delays CRPC and enzalutamide-resistant progression. Plexin B1 sema domain-containing:Fc fusion proteins suppress RTK signaling and cell growth and inhibit CRPC progression of LNCaP xenografts post-castration SEMA3C inhibition represents a novel therapeutic strategy for treatment of advanced prostate cancer.

生长因子受体酪氨酸激酶（RTK）通路的激活是介导癌症生长、存活和治疗耐药的关键机制。同源配体在这些 RTK 通路的自分泌或旁分泌刺激中起着至关重要的作用。在这里，我们表明 SEMA3C 通过 Plexin B1 以配体非依赖性的方式驱动包括 EGFR、ErbB2 和 MET 在内的多种 RTK 的激活。SEMA3C 的表达水平在去势抵抗性前列腺癌（CRPC）中增加，在这种情况下，它促进癌细胞生长并抵抗雄激素受体通路抑制。SEMA3C 抑制可延迟 CRPC 和恩杂鲁胺耐药的进展。Plexin B1 结构域包含：Fc 融合蛋白抑制 RTK 信号和细胞生长，并抑制去势后 LNCaP 异种移植物的 CRPC 进展 SEMA3C 抑制代表了治疗晚期前列腺癌的一种新的治疗策略。