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

ABSTRACT: 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.

SUBMITTER: Garvey CM

PROVIDER: S-EPMC7352975 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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

Garvey Colleen M CM Lau Roy R Sanchez Alyssa A Sun Ren X RX Fong Emma J EJ Doche Michael E ME Chen Oscar O Jusuf Anthony A Lenz Heinz-Josef HJ Larson Brent B Mumenthaler Shannon M SM

Cancers 20200528 6

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, whil ...[more]

PMID: 32481658

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Project description:Long non-coding RNAs (lncRNAs) are involved in the pathology of various tumors, including colorectal cancer (CRC). The crosstalk between carcinoma- associated fibroblasts (CAFs) and cancer cells in the tumor microenvironment promotes tumor development and confers chemoresistance. In this study, we further investigated the underlying tumor-promoting roles of CAFs and the molecular mediators involved in these processes. Methods: The AOM/DSS-induced colitis-associated cancer (CAC) mouse model was established, and RNA sequencing was performed. Small interfering RNA (siRNA) sequences were used to knock down H19. Cell apoptosis was measured by flow cytometry. SW480 cells with H19 stably knocked down were used to establish a xenograft model. The indicated protein levels in xenograft tumor tissues were confirmed by immunohistochemistry assay, and cell apoptosis was analyzed by TUNEL apoptosis assay. RNA-FISH and immunofluorescence assays were performed to assess the expression of H19 in tumor stroma and cancer nests. The AldeRed ALDH detection assay was performed to detect intracellular aldehyde dehydrogenase (ALDH) enzyme activity. Isolated exosomes were identified by transmission electron microscopy, nanoparticle tracking and Western blotting. Results: H19 was highly expressed in the tumor tissues of CAC mice compared with the expression in normal colon tissues. The up-regulation of H19 was also confirmed in CRC patient samples at different tumor node metastasis (TNM) stages. Moreover, H19 was associated with the stemness of colorectal cancer stem cells (CSCs) in CRC specimens. H19 promoted the stemness of CSCs and increased the frequency of tumor-initiating cells. RNA-FISH showed higher expression of H19 in tumor stroma than in cancer nests. Of note, H19 was enriched in CAF-derived conditioned medium and exosomes, which in turn promoted the stemness of CSCs and the chemoresistance of CRC cells in vitro and in vivo. Furthermore, H19 activated the ?-catenin pathway via acting as a competing endogenous RNA sponge for miR-141 in CRC, while miR-141 significantly inhibited the stemness of CRC cells. Conclusion: CAFs promote the stemness and chemoresistance of CRC by transferring exosomal H19. H19 activated the ?-catenin pathway via acting as a competing endogenous RNA sponge for miR-141, while miR-141 inhibited the stemness of CRC cells. Our findings indicate that H19 expressed by CAFs of the colorectal tumor stroma contributes to tumor development and chemoresistance.

Project description:BackgroundColorectal cancer (CRC) is one of the leading causes of cancer-related death worldwide, however, the mechanisms of CRC progression remain obscure. The present study investigated the clinical significance and functional role of long noncoding RNA (lncRNA) GIHCG in CRC.MethodsExpression of GIHCG was detected by quantitative real time polymerase chain reaction (qRT-PCR) in seven CRC cell lines and 110 CRC tissues. Comparison of clinicopathological characteristics in the high GIHCG expression group and the low GIHCG expression group was performed. The overall survival (OS) and progression-free survival (PFS) of the patients were depicted with Kaplan-Meier test and compared with Log-rank test. Univariate and multivariate analyses were carried out to detect the risk factors for poor OS and PFS. In addition, expression of GIHCG was silenced with siRNAs in LoVo cells and overexpressed with pcDNA3.1-GIHCG vector in SW480 cells, respectively. And the Transwell assay, Matrigel assay, colony formation assay and Cell Counting Kit-8 assay (CCK-8) were performed to investigate the role of GIHCG in the migration, invasion and proliferation of CRC cells. Besides, the role of GIHCG in chemoresistance was also detected.ResultsGIHCG was overexpressed in seven CRC cell lines and 110 CRC tissues. High GIHCG expression was correlated with lymphovascular invasion, lymph node metastasis, distant metastasis and advanced TNM stages. Moreover, patients with high GIHCG expression had much poorer OS and PFS rates. Besides, high GIHCG expression was identified as an independent risk factor for poor OS and PFS. The Transwell assay and the Matrigel assay discovered that GIHCG deficiency inhibited cell migration and invasion, while ectopic expression of GIHCG promoted migration and invasion. Besides, the colony formation assay and the CCK-8 assay verified that GIHCG increased cell proliferation ability. By establishing 5-fluorouracil (5-FU) and Oxaliplatin (Oxa)-resistant LoVo cells and SW480 cells, we found chemoresistant CRC cells had much higher expression levels of GIHCG. Also, GIHCG facilitated cell survival under 5-FU or Oxa treatment. Furthermore, silencing of GIHCG notably reduced the improved cell survival rates of 5-FU or Oxa-resistant LoVo cells compared with control cells.ConclusionGIHCG contributes to cancer progression and chemoresistance and indicates poor prognosis in CRC. GIHCG may be a promising prognostic biomarker and therapeutic target in CRC.

Dataset Information

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

Publications

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

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