Next Article in Journal
Choline PET/CT in Multiple Myeloma
Next Article in Special Issue
CXCR4 Inhibition Enhances Efficacy of FLT3 Inhibitors in FLT3-Mutated AML Augmented by Suppressed TGF-β Signaling
Previous Article in Journal
Correction: Teeuwssen and Fodde; Colon Cancer Heterogeneity and Phenotypic Plasticity in Metastasis Formation. Cancers 2019, 11(9), 1368
 
 
Article

Anti-EGFR Therapy Induces EGF Secretion by Cancer-Associated Fibroblasts to Confer Colorectal Cancer Chemoresistance

1
Lawrence J. Ellison Institute for Transformative Medicine, University of Southern California, Los Angeles, CA 90033, USA
2
Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
3
Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(6), 1393; https://doi.org/10.3390/cancers12061393
Received: 23 April 2020 / Revised: 13 May 2020 / Accepted: 22 May 2020 / Published: 28 May 2020
(This article belongs to the Special Issue Targeting the Tumor Microenvironment)
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. View Full-Text
Keywords: colorectal cancer; cancer-associated fibroblasts; epidermal growth factor; cetuximab; drug-resistance; tumor microenvironment colorectal cancer; cancer-associated fibroblasts; epidermal growth factor; cetuximab; drug-resistance; tumor microenvironment
Show Figures

Figure 1

MDPI and ACS Style

Garvey, C.M.; Lau, R.; Sanchez, A.; Sun, R.X.; Fong, E.J.; Doche, M.E.; Chen, O.; Jusuf, A.; Lenz, H.-J.; Larson, B.; Mumenthaler, S.M. Anti-EGFR Therapy Induces EGF Secretion by Cancer-Associated Fibroblasts to Confer Colorectal Cancer Chemoresistance. Cancers 2020, 12, 1393. https://doi.org/10.3390/cancers12061393

AMA Style

Garvey CM, Lau R, Sanchez A, Sun RX, Fong EJ, Doche ME, Chen O, Jusuf A, Lenz H-J, Larson B, Mumenthaler SM. Anti-EGFR Therapy Induces EGF Secretion by Cancer-Associated Fibroblasts to Confer Colorectal Cancer Chemoresistance. Cancers. 2020; 12(6):1393. https://doi.org/10.3390/cancers12061393

Chicago/Turabian Style

Garvey, Colleen M., Roy Lau, Alyssa Sanchez, Ren X. Sun, Emma J. Fong, Michael E. Doche, Oscar Chen, Anthony Jusuf, Heinz-Josef Lenz, Brent Larson, and Shannon M. Mumenthaler. 2020. "Anti-EGFR Therapy Induces EGF Secretion by Cancer-Associated Fibroblasts to Confer Colorectal Cancer Chemoresistance" Cancers 12, no. 6: 1393. https://doi.org/10.3390/cancers12061393

Find Other Styles
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Back to TopTop