INSERM, UMRS1138, Laboratory of Integrative Cancer Immunology, F-75006 Paris, France. Université Paris Descartes, Sorbonne Paris Cité, UMRS1138, F-75006 Paris, France. Sorbonne Universités, UPMC Univ Paris 06, UMRS1138, Centre de Recherche des Cordeliers, F-75006 Paris, France.
INSERM, UMRS1138, Laboratory of Integrative Cancer Immunology, F-75006 Paris, France. Université Paris Descartes, Sorbonne Paris Cité, UMRS1138, F-75006 Paris, France. Sorbonne Universités, UPMC Univ Paris 06, UMRS1138, Centre de Recherche des Cordeliers, F-75006 Paris, France. AstraZeneca, Cambridge CB4 OWG, UK.
Sci Transl Med. 2016 Feb 24;8(327):327ra26. doi: 10.1126/scitranslmed.aad6352.
Although distant metastases account for most of the deaths in cancer patients, fundamental questions regarding mechanisms that promote or inhibit metastasis remain unanswered. We show the impact of mutations, genomic instability, lymphatic and blood vascularization, and the immune contexture of the tumor microenvironment on synchronous metastases in large cohorts of colorectal cancer patients. We observed large genetic heterogeneity among primary tumors, but no major differences in chromosomal instability or key cancer-associated mutations. Similar patterns of cancer-related gene expression levels were observed between patients. No cancer-associated genes or pathways were associated with M stage. Instead, mutations of FBXW7 were associated with the absence of metastasis and correlated with increased expression of T cell proliferation and antigen presentation functions. Analyzing the tumor microenvironment, we observed two hallmarks of the metastatic process: decreased presence of lymphatic vessels and reduced immune cytotoxicity. These events could be the initiating factors driving both synchronous and metachronous metastases. Our data demonstrate the protective impact of the Immunoscore, a cytotoxic immune signature, and increased marginal lymphatic vessels, against the generation of distant metastases, regardless of genomic instability.
尽管远处转移是癌症患者死亡的主要原因，但促进或抑制转移的机制的基本问题仍未得到解答。我们展示了突变、基因组不稳定性、淋巴管和血管生成以及肿瘤微环境的免疫结构对大量结直肠癌患者同步转移的影响。我们观察到原发性肿瘤之间存在很大的遗传异质性，但染色体不稳定性或关键癌症相关突变没有明显差异。患者之间观察到相似的癌症相关基因表达水平模式。没有与 M 期相关的癌症相关基因或途径。相反，FBXW7 的突变与无转移相关，并与 T 细胞增殖和抗原呈递功能的表达增加相关。分析肿瘤微环境，我们观察到转移过程的两个特征：淋巴血管存在减少和免疫细胞毒性降低。这些事件可能是驱动同步和异时转移的起始因素。我们的数据表明，免疫评分（一种细胞毒性免疫特征）和边缘淋巴血管增加的保护性影响，可以防止远处转移的发生，而与基因组不稳定性无关。
