期刊
GASTROENTEROLOGY
卷 162, 期 3, 页码 890-906出版社
W B SAUNDERS CO-ELSEVIER INC
DOI: 10.1053/j.gastro.2021.11.037
关键词
Colorectal Cancer; Tumor Microenvironment; Alpha-Smooth Muscle Actin (alpha SMA); CD146
资金
- National Health and Medical Research Council [APP1156391, APP1081852, APP1140236, APP1099283]
- Cancer Council SA Beat Cancer Project on behalf of its donors
- State Government of South Australia through the Department of Health [MCF0418, PRF1117]
- Ministry of Education, Culture, Sports, Science and Technology of Japan [26221304]
- AMED-CREST (Japan Agency for Medical Research and Development, Core Research for Evolutional Science and Technology) [20gm0810007h0105, 20gm1210009s0102]
- Project for Cancer Research and Therapeutic Evolution (P-CREATE) from AMED [20cm0106377h0001, 21cm0106704h0002]
- Japan Society for the Promotion of Science Overseas Challenge Program for Young Researchers
- Takeda Science Foundation Fellowship
- Lions Medical Research Foundation Scholarship
- Greaton International PhD Scholarship
In colorectal cancer, ACTA2(+) cancer-associated fibroblasts (CAFs) emerge through proliferation from intestinal pericryptal leptin receptor (Lepr)(+) cells. These Lepr-lineage CAFs express melanoma cell adhesion molecule (MCAM), which is inversely associated with patient survival. Knockout of stromal Mcam attenuates orthotopically injected colorectal tumoroid growth and improves survival through decreased tumor-associated macrophage recruitment. The fibroblast MCAM interacts with interleukin-1 receptor 1 to promote macrophage chemotaxis.
BACKGROUND & AIMS: 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. METHODS: To elucidate CAF origins, we used a colitis-associated CRC mouse model in 5 different fate mapping mouse lines with 5-bromodeoxyuridine dosing. RNA sequencing of fluorescence-activated cell sorting-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 colons of knockout mice to assess the mechanism by which the stromal gene contributes to colorectal tumorigenesis.RESULTS: 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 that we identified with the use of RNA sequencing. High MCAM expression induced by transforming growth factor beta 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 kappa B-IL34/CCL8 signaling that promotes macrophage chemotaxis. CONCLUSIONS: 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.
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