The Origin and Contribution of Cancer-Associated Fibroblasts in Colorectal Carcinogenesis.
The Origin and Contribution of Cancer-Associated Fibroblasts in Colorectal Carcinogenesis.
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癌症相关成纤维细胞在结直肠癌发生中的起源和贡献。
DOI：
10.1053/j.gastro.2021.11.037
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发表时间：
2022-03
期刊：
影响因子：
29.4
通讯作者：
Worthley DL
中科院分区：
文献类型：
--
作者：
Kobayashi H;Gieniec KA;Lannagan TRM;Wang T;Asai N;Mizutani Y;Iida T;Ando R;Thomas EM;Sakai A;Suzuki N;Ichinose M;Wright JA;Vrbanac L;Ng JQ;Goyne J;Radford G;Lawrence MJ;Sammour T;Hayakawa Y;Klebe S;Shin AE;Asfaha S;Bettington ML;Rieder F;Arpaia N;Danino T;Butler LM;Burt AD;Leedham SJ;Rustgi AK;Mukherjee S;Takahashi M;Wang TC;Enomoto A;Woods SL;Worthley DL
癌相关成纤维细胞（CAF）在结直肠癌（CRC）的进展中起重要作用，并预测CRC患者的不良预后。然而，CAF的细胞起源仍然未知，使得治疗靶向这些细胞具有挑战性。在这里，我们的目的是确定与不良预后相关的结直肠CAF的起源和贡献。为了阐明CAF的起源，我们在5种不同的BrdU剂量的命运图谱小鼠系中使用了结肠炎相关CRC小鼠模型。进行荧光激活细胞分选（FACS）纯化的CRC CAF的RNA测序以鉴定CAF中的潜在治疗靶标。为了检查基质靶点的预后意义，使用CRC患者RNA测序数据和组织微阵列。将CRC类器官注射到基因敲除小鼠的结肠中，以评估基质基因促进结直肠肿瘤发生的机制。我们的谱系追踪研究显示，在CRC中，许多ACTA 2 + CAF通过肠内周瘦素受体（Lepr）+细胞增殖而出现。反过来，这些麻风病谱系CAF表达黑色素瘤细胞粘附分子（MCAM），这是我们使用RNA测序鉴定的CRC基质特异性标志物。TGF-β诱导的高MCAM表达与人CRC患者的生存率呈负相关。在小鼠中，间质Mcam敲除通过减少肿瘤相关巨噬细胞募集来减弱原位注射的结直肠类肿瘤生长并改善存活。从机制上讲，成纤维细胞MCAM与白细胞介素-1受体1相互作用，以增强核因子-IL 3B-IL 34/CCL 8信号传导，从而促进巨噬细胞趋化性。在结直肠癌发生过程中，髓周麻风细胞系细胞增殖产生MCAM+ CAF，形成促肿瘤免疫微环境。阻止麻风谱系CAF的扩增/分化或抑制MCAM活性可能是CRC的有效治疗方法。在结直肠癌（CRC）中，组织驻留的LepR谱系基质细胞是MCAM+免疫调节性癌症相关成纤维细胞的主要贡献者。了解这种基质演变已经发现了CRC的新的潜在治疗靶点。
Cancer-associated fibroblasts (CAFs) play an important role in colorectal cancer (CRC) progression and predict poor prognosis in CRC patients. However, the cellular origins of CAFs remain unknown, making it challenging to therapeutically target these cells. Here, we aimed to identify the origins and contribution of colorectal CAFs associated with poor prognosis. To elucidate CAF origins, we used a colitis-associated CRC mouse model in 5 different fate-mapping mouse lines with BrdU dosing. RNA-sequencing of fluorescence-activated cell sorting (FACS)-purified CRC CAFs was performed to identify a potential therapeutic target in CAFs. To examine the prognostic significance of the stromal target, CRC patient RNA-sequencing data and tissue microarray were used. CRC organoids were injected into the colon of knockout mice to assess the mechanism by which the stromal gene contributes to colorectal tumorigenesis. Our lineage-tracing studies revealed that, in CRC, many ACTA2+ CAFs emerge through proliferation from intestinal pericryptal Leptin receptor (Lepr)+ cells. These Lepr-lineage CAFs, in turn, express melanoma cell adhesion molecule (MCAM), a CRC stroma-specific marker we identified using RNA-sequencing. High MCAM expression induced by TGF-β was inversely associated with patient survival in human CRC. In mice, stromal Mcam knockout attenuated orthotopically injected colorectal tumoroid growth and improved survival through decreased tumor-associated macrophage recruitment. Mechanistically, fibroblast MCAM interacted with interleukin-1 receptor 1 to augment nuclear factor-ĸB-IL34/CCL8 signaling that promotes macrophage chemotaxis. In colorectal carcinogenesis, pericryptal Lepr-lineage cells proliferate to generate MCAM+ CAFs that shape the tumor-promoting immune microenvironment. Preventing the expansion/differentiation of Lepr-lineage CAFs or inhibiting MCAM activity could be effective therapeutic approaches for CRC. In colorectal cancer (CRC), tissue-resident LepR-lineage stromal cells are a major contributor to MCAM+ immunoregulatory cancer-associated fibroblasts. Understanding this stromal evolution has uncovered novel potential therapeutic targets for CRC.
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DOI：
10.1073/pnas.1600363113
发表时间：
2016-07-05
影响因子：
11.1
作者：
Arina, Ainhoa;Idel, Christian;Schreiber, Hans
通讯作者：
Schreiber, Hans
影响因子：
50.3
作者：
Özdemir BC;Pentcheva-Hoang T;Carstens JL;Zheng X;Wu CC;Simpson TR;Laklai H;Sugimoto H;Kahlert C;Novitskiy SV;De Jesus-Acosta A;Sharma P;Heidari P;Mahmood U;Chin L;Moses HL;Weaver VM;Maitra A;Allison JP;LeBleu VS;Kalluri R
通讯作者：
Kalluri R
影响因子：
21.3
作者：
Decker M;Martinez-Morentin L;Wang G;Lee Y;Liu Q;Leslie J;Ding L
通讯作者：
Ding L
影响因子：
5.9
作者：
Kurashige M;Kohara M;Ohshima K;Tahara S;Hori Y;Nojima S;Wada N;Ikeda JI;Miyamura K;Ito M;Morii E
通讯作者：
Morii E
影响因子：
20.3
作者：
Corselli, Mirko;Chin, Chee Jia;Peault, Bruno
通讯作者：
Peault, Bruno