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The Origin and Contribution of Cancer-Associated Fibroblasts in Colorectal Carcinogenesis.
Kobayashi, Hiroki; Gieniec, Krystyna A; Lannagan, Tamsin R M; Wang, Tongtong; Asai, Naoya; Mizutani, Yasuyuki; Iida, Tadashi; Ando, Ryota; Thomas, Elaine M; Sakai, Akihiro; Suzuki, Nobumi; Ichinose, Mari; Wright, Josephine A; Vrbanac, Laura; Ng, Jia Q; Goyne, Jarrad; Radford, Georgette; Lawrence, Matthew J; Sammour, Tarik; Hayakawa, Yoku; Klebe, Sonja; Shin, Alice E; Asfaha, Samuel; Bettington, Mark L; Rieder, Florian; Arpaia, Nicholas; Danino, Tal; Butler, Lisa M; Burt, Alastair D; Leedham, Simon J; Rustgi, Anil K; Mukherjee, Siddhartha; Takahashi, Masahide; Wang, Timothy C; Enomoto, Atsushi; Woods, Susan L; Worthley, Daniel L.
Affiliation
  • Kobayashi H; Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia; South Australian Health and Medical Research Institute (SAHMRI), Adelaide, South Australia, Australia; Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan; Division of Mole
  • Gieniec KA; Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia; South Australian Health and Medical Research Institute (SAHMRI), Adelaide, South Australia, Australia.
  • Lannagan TRM; Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia; South Australian Health and Medical Research Institute (SAHMRI), Adelaide, South Australia, Australia.
  • Wang T; Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia; South Australian Health and Medical Research Institute (SAHMRI), Adelaide, South Australia, Australia.
  • Asai N; Department of Molecular Pathology, Graduate School of Medicine, Fujita Health University, Toyoake, Aichi, Japan.
  • Mizutani Y; Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan; Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
  • Iida T; Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan; Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
  • Ando R; Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
  • Thomas EM; Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia; South Australian Health and Medical Research Institute (SAHMRI), Adelaide, South Australia, Australia.
  • Sakai A; Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
  • Suzuki N; Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia; South Australian Health and Medical Research Institute (SAHMRI), Adelaide, South Australia, Australia; Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
  • Ichinose M; Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia; South Australian Health and Medical Research Institute (SAHMRI), Adelaide, South Australia, Australia.
  • Wright JA; South Australian Health and Medical Research Institute (SAHMRI), Adelaide, South Australia, Australia.
  • Vrbanac L; Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia; South Australian Health and Medical Research Institute (SAHMRI), Adelaide, South Australia, Australia.
  • Ng JQ; Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia; South Australian Health and Medical Research Institute (SAHMRI), Adelaide, South Australia, Australia.
  • Goyne J; Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia; South Australian Health and Medical Research Institute (SAHMRI), Adelaide, South Australia, Australia.
  • Radford G; Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia; South Australian Health and Medical Research Institute (SAHMRI), Adelaide, South Australia, Australia.
  • Lawrence MJ; Colorectal Unit, Department of Surgery, Royal Adelaide Hospital, Adelaide, South Australia, Australia.
  • Sammour T; Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia; South Australian Health and Medical Research Institute (SAHMRI), Adelaide, South Australia, Australia; Colorectal Unit, Department of Surgery, Royal Adelaide Hospital, Adelaide, South Australia, Australia.
  • Hayakawa Y; Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
  • Klebe S; Department of Anatomical Pathology, Flinders Medical Centre, Bedford Park, Adelaide, South Australia, Australia.
  • Shin AE; Pathology and Laboratory Medicine, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada.
  • Asfaha S; Department of Medicine, University of Western Ontario, London, Ontario, Canada.
  • Bettington ML; Envoi Specialist Pathologists, Kelvin Grove, Queensland, Australia; Faculty of Medicine, University of Queensland, Herston, Queensland, Australia; QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
  • Rieder F; Department of Gastroenterology, Hepatology, and Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA; Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA.
  • Arpaia N; Department of Microbiology and Immunology, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York, USA; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York, USA.
  • Danino T; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York, USA; Department of Biomedical Engineering, Columbia University, New York, New York, USA.
  • Butler LM; Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia; South Australian Health and Medical Research Institute (SAHMRI), Adelaide, South Australia, Australia.
  • Burt AD; Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia; Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom.
  • Leedham SJ; Intestinal Stem Cell Biology Lab, Wellcome Trust Centre Human Genetics, University of Oxford, Oxford, United Kingdom.
  • Rustgi AK; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York, USA.
  • Mukherjee S; Department of Medicine and Irving Cancer Research Center, Columbia University, New York, New York, USA.
  • Takahashi M; Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan; Division of Molecular Pathology, Center for Neurological Disease and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan; International Center for Cell and Gene Therapy, Fujita Healt
  • Wang TC; Department of Medicine and Irving Cancer Research Center, Columbia University, New York, New York, USA.
  • Enomoto A; Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan. Electronic address: enomoto@iar.nagoya-u.ac.jp.
  • Woods SL; Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia; South Australian Health and Medical Research Institute (SAHMRI), Adelaide, South Australia, Australia. Electronic address: susan.woods@adelaide.edu.au.
  • Worthley DL; South Australian Health and Medical Research Institute (SAHMRI), Adelaide, South Australia, Australia; GastroIntestinal Endoscopy, Lutwyche, Queensland, Australia. Electronic address: dan@colonoscopyclinic.com.au.
Gastroenterology ; 162(3): 890-906, 2022 03.
Article in En | MEDLINE | ID: mdl-34883119
ABSTRACT
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 ß 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 κB-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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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Colorectal Neoplasms / Cell Lineage / Mesenchymal Stem Cells / Carcinogenesis / Cancer-Associated Fibroblasts Type of study: Prognostic_studies / Risk_factors_studies Limits: Adult / Aged / Aged80 / Animals / Female / Humans / Male / Middle aged Language: En Journal: Gastroenterology Year: 2022 Type: Article
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Colorectal Neoplasms / Cell Lineage / Mesenchymal Stem Cells / Carcinogenesis / Cancer-Associated Fibroblasts Type of study: Prognostic_studies / Risk_factors_studies Limits: Adult / Aged / Aged80 / Animals / Female / Humans / Male / Middle aged Language: En Journal: Gastroenterology Year: 2022 Type: Article