Certain matrix metalloproteinase (MMP) family proteins have been associated with cell proliferation and invasion in aggressive cancers. However, attempts to target the MMPs with the hope of treating tumors have thus far failed. In this issue of the JCI, Ragusa and coworkers identified an intestinal cancer subgroup of slow-growing, chemotherapy-resistant, and very aggressive matrix-rich tumors that mimic a hard-to-treat colorectal cancer subtype in humans. These tumors showed downregulated levels of the transcription factor prospero homeobox protein 1 (PROX1), which relieved repression of the matrix metalloproteinase MMP14. Upregulated MMP14 levels correlated with blood vessel dysfunction and a lack of cytotoxic T cells. Notably, blockade of proangiogenic factors in combination with stimulation of the CD40 pathway in the mouse cancer model boosted cytotoxic T cell infiltration. The study illustrates how combinatorial treatments for aggressive, T cell-deficient cancers can launch an antitumor immune response.

中文翻译：

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基质金属蛋白酶MMP14如何促进结直肠癌的进展。

某些基质金属蛋白酶（MMP）家族蛋白与侵袭性癌症中的细胞增殖和侵袭有关。然而，迄今为止，以治疗肿瘤为希望的靶向MMP的尝试失败了。在JCI的这一期中，Ragusa和同事们确定了一个肠道癌亚组，其生长缓慢，对化疗具有抗药性，并且具有非常富侵略性的富含基质的肿瘤，可模拟人类难以治疗的结直肠癌亚型。这些肿瘤显示出转录因子prospero同源盒蛋白1（PROX1）的水平下调，从而减轻了基质金属蛋白酶MMP14的抑制作用。MMP14水平上调与血管功能障碍和缺乏细胞毒性T细胞相关。值得注意的是 在小鼠癌症模型中阻断促血管生成因子并刺激CD40途径可增强细胞毒性T细胞浸润。这项研究说明了针对侵袭性，T细胞缺陷型癌症的联合治疗如何能够引发抗肿瘤免疫反应。