Systemic treatment of hepatocellular carcinoma (HCC) targets the tumor microenvironment (TME) by combining immunotherapy with angiogenesis inhibitors. Cancer-associated fibroblasts (CAF) are important components of the TME, however their targeting in clinics remains challenging. To this end, the existence of tumor supressing CAF and their poor characterisation is a major conundrum. Starting from proteomics and single cell analysis, we outline CAF heterogeneity in HCC and describe a subtype of CAF that express a novel tumor-related protein prolargin. Upon secretion prolargin is deposited in the TME where its levels positively correlate with patient outcome (HR=0.37; p=0.01). In vivo, tumors with lower prolargin expression display faster progression (5-fold; p=0.01) and stronger angiogenesis. Mechanistically, aggressive HCC cells degrade prolargin using matrix metalloprotease 3 (MMP3). We show that prolargin binds and inhibits several growth factors, key to tumor progression. Inhibiting prolargin degradation combined with sorafenib, demonstrated superior tumor control compared to sorafenib treatment alone. In conclusion, prolargin-expressing CAF have tumor-antagonizing properties. Stabilizing prolargin tumoral levels should be considered for systemic therapy of HCC, involving CAF in existing TME targeting.

中文翻译：

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肿瘤拮抗成纤维细胞分泌普罗拉金作为肝细胞癌的肿瘤抑制因子。

肝细胞癌（HCC）的系统治疗通过将免疫疗法与血管生成抑制剂相结合来靶向肿瘤微环境（TME）。癌症相关的成纤维细胞（CAF）是TME的重要组成部分，但是其在临床中的靶向性仍然具有挑战性。为此，存在抑制肿瘤的CAF及其不良的表征是一个主要的难题。从蛋白质组学和单细胞分析开始，我们概述了肝癌中CAF的异质性，并描述了表达新型肿瘤相关蛋白prolargin的CAF亚型。分泌后，孕激素会沉积在TME中，其水平与患者预后呈正相关（HR = 0.37； p = 0.01）。在体内，prolargin表达较低的肿瘤显示出更快的进展（5倍； p = 0.01）和更强的血管生成。机械上，侵袭性HCC细胞使用基质金属蛋白酶3（MMP3）降解prolargin。我们表明，prolargin结合并抑制几种生长因子，这是肿瘤进展的关键。与单独的索拉非尼治疗相比，与索拉非尼组合使用抑制prolargin降解表现出更好的肿瘤控制能力。总之，表达催乳激素的CAF具有抗肿瘤作用。对于HCC的全身治疗，应考虑将稳定的原发性肿瘤水平考虑在内，将CAF纳入现有TME靶向治疗。