Anti-EGFR Therapy Induces EGF Secretion by Cancer-Associated Fibroblasts to Confer Colorectal Cancer Chemoresistance
Targeted agents have improved the efficacy of chemotherapy for cancer patients, however, there remains a lack of understanding of how these therapies affect the unsuspecting bystanders of the stromal microenvironment. Cetuximab, a monoclonal antibody therapy targeting the epidermal growth factor rec...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-05-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/12/6/1393 |
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| author | Colleen M. Garvey Roy Lau Alyssa Sanchez Ren X. Sun Emma J. Fong Michael E. Doche Oscar Chen Anthony Jusuf Heinz-Josef Lenz Brent Larson Shannon M. Mumenthaler |
| author_facet | Colleen M. Garvey Roy Lau Alyssa Sanchez Ren X. Sun Emma J. Fong Michael E. Doche Oscar Chen Anthony Jusuf Heinz-Josef Lenz Brent Larson Shannon M. Mumenthaler |
| author_sort | Colleen M. Garvey |
| collection | DOAJ |
| description | Targeted agents have improved the efficacy of chemotherapy for cancer patients, however, there remains a lack of understanding of how these therapies affect the unsuspecting bystanders of the stromal microenvironment. Cetuximab, a monoclonal antibody therapy targeting the epidermal growth factor receptor (EGFR), is given in combination with chemotherapy as the standard of care for a subset of metastatic colorectal cancer patients. The overall response to this treatment is underwhelming and, while genetic mutations that confer resistance have been identified, it is still not known why this drug is ineffective for some patients. We discovered that cancer-associated fibroblasts (CAFs), a major cellular subset of the tumor stroma, can provide a source of cancer cell resistance. Specifically, we observed that upon treatment with cetuximab, CAFs increased their secretion of EGF, which was sufficient to render neighboring cancer cells resistant to cetuximab treatment through sustained mitogen-activated protein kinases (MAPK) signaling. Furthermore, we show the cetuximab-induced EGF secretion to be specific to CAFs and not to cancer cells or normal fibroblasts. Altogether, this work emphasizes the importance of the tumor microenvironment and considering the potential unintended consequences of therapeutically targeting cancer-driving proteins on non-tumorigenic cell types. |
| first_indexed | 2024-03-10T19:32:13Z |
| format | Article |
| id | doaj.art-c002135550fb4ced87b78a46a545dcb0 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T19:32:13Z |
| publishDate | 2020-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-c002135550fb4ced87b78a46a545dcb02023-11-20T02:03:00ZengMDPI AGCancers2072-66942020-05-01126139310.3390/cancers12061393Anti-EGFR Therapy Induces EGF Secretion by Cancer-Associated Fibroblasts to Confer Colorectal Cancer ChemoresistanceColleen M. Garvey0Roy Lau1Alyssa Sanchez2Ren X. Sun3Emma J. Fong4Michael E. Doche5Oscar Chen6Anthony Jusuf7Heinz-Josef Lenz8Brent Larson9Shannon M. Mumenthaler10Lawrence J. Ellison Institute for Transformative Medicine, University of Southern California, Los Angeles, CA 90033, USALawrence J. Ellison Institute for Transformative Medicine, University of Southern California, Los Angeles, CA 90033, USALawrence J. Ellison Institute for Transformative Medicine, University of Southern California, Los Angeles, CA 90033, USALawrence J. Ellison Institute for Transformative Medicine, University of Southern California, Los Angeles, CA 90033, USALawrence J. Ellison Institute for Transformative Medicine, University of Southern California, Los Angeles, CA 90033, USALawrence J. Ellison Institute for Transformative Medicine, University of Southern California, Los Angeles, CA 90033, USALawrence J. Ellison Institute for Transformative Medicine, University of Southern California, Los Angeles, CA 90033, USALawrence J. Ellison Institute for Transformative Medicine, University of Southern California, Los Angeles, CA 90033, USADivision of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USADepartment of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USALawrence J. Ellison Institute for Transformative Medicine, University of Southern California, Los Angeles, CA 90033, USATargeted agents have improved the efficacy of chemotherapy for cancer patients, however, there remains a lack of understanding of how these therapies affect the unsuspecting bystanders of the stromal microenvironment. Cetuximab, a monoclonal antibody therapy targeting the epidermal growth factor receptor (EGFR), is given in combination with chemotherapy as the standard of care for a subset of metastatic colorectal cancer patients. The overall response to this treatment is underwhelming and, while genetic mutations that confer resistance have been identified, it is still not known why this drug is ineffective for some patients. We discovered that cancer-associated fibroblasts (CAFs), a major cellular subset of the tumor stroma, can provide a source of cancer cell resistance. Specifically, we observed that upon treatment with cetuximab, CAFs increased their secretion of EGF, which was sufficient to render neighboring cancer cells resistant to cetuximab treatment through sustained mitogen-activated protein kinases (MAPK) signaling. Furthermore, we show the cetuximab-induced EGF secretion to be specific to CAFs and not to cancer cells or normal fibroblasts. Altogether, this work emphasizes the importance of the tumor microenvironment and considering the potential unintended consequences of therapeutically targeting cancer-driving proteins on non-tumorigenic cell types.https://www.mdpi.com/2072-6694/12/6/1393colorectal cancercancer-associated fibroblastsepidermal growth factorcetuximabdrug-resistancetumor microenvironment |
| spellingShingle | Colleen M. Garvey Roy Lau Alyssa Sanchez Ren X. Sun Emma J. Fong Michael E. Doche Oscar Chen Anthony Jusuf Heinz-Josef Lenz Brent Larson Shannon M. Mumenthaler Anti-EGFR Therapy Induces EGF Secretion by Cancer-Associated Fibroblasts to Confer Colorectal Cancer Chemoresistance Cancers colorectal cancer cancer-associated fibroblasts epidermal growth factor cetuximab drug-resistance tumor microenvironment |
| title | Anti-EGFR Therapy Induces EGF Secretion by Cancer-Associated Fibroblasts to Confer Colorectal Cancer Chemoresistance |
| title_full | Anti-EGFR Therapy Induces EGF Secretion by Cancer-Associated Fibroblasts to Confer Colorectal Cancer Chemoresistance |
| title_fullStr | Anti-EGFR Therapy Induces EGF Secretion by Cancer-Associated Fibroblasts to Confer Colorectal Cancer Chemoresistance |
| title_full_unstemmed | Anti-EGFR Therapy Induces EGF Secretion by Cancer-Associated Fibroblasts to Confer Colorectal Cancer Chemoresistance |
| title_short | Anti-EGFR Therapy Induces EGF Secretion by Cancer-Associated Fibroblasts to Confer Colorectal Cancer Chemoresistance |
| title_sort | anti egfr therapy induces egf secretion by cancer associated fibroblasts to confer colorectal cancer chemoresistance |
| topic | colorectal cancer cancer-associated fibroblasts epidermal growth factor cetuximab drug-resistance tumor microenvironment |
| url | https://www.mdpi.com/2072-6694/12/6/1393 |
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