Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.
Oncogene. 2023 Aug;42(34):2578-2588. doi: 10.1038/s41388-023-02777-5. Epub 2023 Jul 19.
Gastrointestinal stromal tumor (GIST) is the most common human sarcoma and is typically driven by a single mutation in the Kit or PDGFRA receptor. While highly effective, tyrosine kinase inhibitors (TKIs) are not curative. The natural ligand for the Kit receptor is Kit ligand (KitL), which exists in both soluble and membrane-bound forms. While KitL is known to stimulate human GIST cell lines in vitro, we used a genetically engineered mouse model of GIST containing a common human KIT mutation to investigate the intratumoral sources of KitL, importance of KitL during GIST oncogenesis, and contribution of soluble KitL to tumor growth in vivo. We discovered that in addition to tumor cells, endothelia and smooth muscle cells produced KitL in Kit tumors, even after imatinib therapy. Genetic reduction of total KitL in tumor cells of Kit mice impaired tumor growth in vivo. Similarly, genetic reduction of tumor cell soluble KitL in Kit mice decreased tumor size. By RNA sequencing, quantitative PCR, and immunohistochemistry, KitL expression was heterogeneous in human GIST specimens. In particular, PDGFRA-mutant tumors had much higher KitL expression than Kit-mutant tumors, suggesting the benefit of Kit activation in the absence of mutant KIT. Serum KitL was higher in GIST patients with tumors resistant to imatinib and in those with tumors expressing more KitL RNA. Overall, KitL supports the growth of GIST at baseline and after imatinib therapy and remains a potential biomarker and therapeutic target.
胃肠道间质瘤（GIST）是最常见的人类肉瘤，通常由 Kit 或 PDGFRA 受体的单一突变驱动。虽然酪氨酸激酶抑制剂（TKI）非常有效，但它们并不是治愈性的。Kit 受体的天然配体是 Kit 配体（KitL），它存在于可溶性和膜结合形式中。虽然 KitL 已知在体外刺激人类 GIST 细胞系，但我们使用含有常见人类 KIT 突变的 GIST 基因工程小鼠模型来研究 KitL 的肿瘤内来源、KitL 在 GIST 发生中的重要性以及可溶性 KitL 对体内肿瘤生长的贡献。我们发现，除了肿瘤细胞外，内皮细胞和平滑肌细胞在 Kit 肿瘤中也产生 KitL，即使在伊马替尼治疗后也是如此。Kit 小鼠肿瘤细胞中总 KitL 的遗传减少损害了体内肿瘤的生长。同样，Kit 小鼠肿瘤细胞可溶性 KitL 的遗传减少也降低了肿瘤大小。通过 RNA 测序、定量 PCR 和免疫组织化学，KitL 在人类 GIST 标本中的表达存在异质性。特别是，PDGFRA 突变型肿瘤的 KitL 表达比 Kit 突变型肿瘤高得多，这表明在没有突变 KIT 的情况下 Kit 激活的益处。对伊马替尼耐药的 GIST 患者和 KitL RNA 表达更高的患者的血清 KitL 更高。总的来说，KitL 支持 GIST 在基线和伊马替尼治疗后的生长，并且仍然是一个潜在的生物标志物和治疗靶点。
