Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2023

Open Access 01-12-2023 | Metastasis | Research

RETRACTED ARTICLE: KRAS activation in gastric cancer stem-like cells promotes tumor angiogenesis and metastasis

Authors: Changhwan Yoon, Jun Lu, Yukyung Jun, Yun-Suhk Suh, Bang-Jin Kim, Jacob E. Till, Jong Hyun Kim, Sara H. Keshavjee, Sandra Ryeom, Sam S. Yoon

Published in: BMC Cancer | Issue 1/2023

Login to get access

Abstract

Our previous work showed that KRAS activation in gastric cancer cells leads to activation of an epithelial-to-mesenchymal transition (EMT) program and generation of cancer stem-like cells (CSCs). Here we analyze how this KRAS activation in gastric CSCs promotes tumor angiogenesis and metastasis. Gastric cancer CSCs were found to secrete pro-angiogenic factors such as vascular endothelial growth factor A (VEGF-A), and inhibition of KRAS markedly reduced secretion of these factors. In a genetically engineered mouse model, gastric tumorigenesis was markedly attenuated when both KRAS and VEGF-A signaling were blocked. In orthotropic implant and experimental metastasis models, silencing of KRAS and VEGF-A using shRNA in gastric CSCs abrogated primary tumor formation, lymph node metastasis, and lung metastasis far greater than individual silencing of KRAS or VEGF-A. Analysis of gastric cancer patient samples using RNA sequencing revealed a clear association between high expression of the gastric CSC marker CD44 and expression of both KRAS and VEGF-A, and high CD44 and VEGF-A expression predicted worse overall survival. In conclusion, KRAS activation in gastric CSCs enhances secretion of pro-angiogenic factors and promotes tumor progression and metastasis.
Appendix
Available only for authorised users
Literature
1.
2.
Wagner AD, Syn NL, Moehler M, et al. Chemotherapy for advanced gastric cancer. Cochrane Database Syst Rev. 2017;8:CD004064.PubMed
3.
Comprehensive molecular characterization of gastric adenocarcinoma. Nature. 2014;513:202–9.CrossRef
4.
Samatar AA, Poulikakos PI. Targeting RAS-ERK signalling in cancer: promises and challenges. Nat Rev Drug Discov. 2014;13:928–42.PubMedCrossRef
5.
Till JE, Yoon C, Kim BJ, et al. Oncogenic KRAS and p53 loss drive gastric tumorigenesis in mice that can be attenuated by E-Cadherin expression. Cancer Res. 2017;77:5349–59.PubMedPubMedCentralCrossRef
6.
Shimada S, Mimata A, Sekine M, et al. Synergistic tumour suppressor activity of E-cadherin and p53 in a conditional mouse model for metastatic diffuse-type gastric cancer. Gut. 2012;61:344–53.PubMedCrossRef
7.
Yoon C, Till J, Cho SJ, et al. KRAS activation in gastric adenocarcinoma stimulates epithelial-to-mesenchymal transition to cancer stem-like cells and promotes metastasis. Mol Cancer Res. 2019;17:1945–57.PubMedPubMedCentralCrossRef
8.
Kim MI, Kim SY, Lee JJ, et al. Prognostic effect of vascular endothelial growth factor and angiogenesis in gastric carcinoma. Cancer Res Treat. 2003;35:218–23.PubMedCrossRef
9.
Park DJ, Thomas NJ, Yoon C, Yoon SS. Vascular endothelial growth factor a inhibition in gastric cancer. Gastric Cancer. 2015;18:33–42.PubMedCrossRef
10.
Wilke H, Muro K, Van Cutsem E, et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014;15:1224–35.PubMedCrossRef
11.
Fuchs CS, Tomasek J, Yong CJ, et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2014;383:31–9.PubMedCrossRef
12.
UKCCCR guidelines for the use of cell lines in cancer research. Br J Cancer 2000; 82: 1495–1509.
13.
Vlachogiannis G, Hedayat S, Vatsiou A, et al. Patient-derived organoids model treatment response of metastatic gastrointestinal cancers. Science. 2018;359:920–6.PubMedPubMedCentralCrossRef
14.
Jun Y, Suh YS, Park S, et al. Comprehensive analysis of alternative splicing in gastric cancer identifies epithelial-mesenchymal transition subtypes associated with survival. Cancer Res. 2022;82:543–55.PubMedCrossRef
15.
Gu Z, Eils R, Schlesner M. Complex heatmaps reveal patterns and correlations in multidimensional genomic data. Bioinformatics. 2016;32:2847–9.PubMedCrossRef
16.
Subramanian A, Tamayo P, Mootha VK, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005;102:15545–50.PubMedPubMedCentralCrossRef
17.
18.
Yoon C, Park DJ, Schmidt B, et al. CD44 expression denotes a subpopulation of gastric cancer cells in which Hedgehog signaling promotes chemotherapy resistance. Clin Cancer Res. 2014;20:3974–88.PubMedPubMedCentralCrossRef
19.
Prewett M, Huber J, Li Y, et al. Antivascular endothelial growth factor receptor (fetal liver kinase 1) monoclonal antibody inhibits tumor angiogenesis and growth of several mouse and human tumors. Cancer Res. 1999;59:5209–18.PubMed
20.
21.
Jackson DG. Hyaluronan in the lymphatics: the key role of the hyaluronan receptor LYVE-1 in leucocyte trafficking. Matrix Biol. 2019;78–79:219–35.PubMedCrossRef
22.
Cristescu R, Lee J, Nebozhyn M, et al. Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes. Nat Med. 2015;21:449–56.PubMedCrossRef
23.
Lin JX, Yoon C, Li P, et al. Increased CD44 expression and mek activity predict worse prognosis in gastric adenocarcinoma patients undergoing gastrectomy. J Gastrointest Surg. 2021;25:1147–55.PubMedCrossRef
24.
Alison MR, Lin WR, Lim SM, Nicholson LJ. Cancer stem cells: in the line of fire. Cancer Treat Rev. 2012;38:589–98.PubMedCrossRef
25.
26.
27.
28.
Min J, Vega PN, Engevik AC, et al. Heterogeneity and dynamics of active Kras-induced dysplastic lineages from mouse corpus stomach. Nat Commun. 2019;10:5549.PubMedPubMedCentralCrossRef
29.
30.
Blaj C, Schmidt EM, Lamprecht S, et al. Oncogenic effects of high MAPK activity in colorectal cancer mark progenitor cells and persist irrespective of RAS mutations. Cancer Res. 2017;77:1763–74.PubMedCrossRef
31.
Moon BS, Jeong WJ, Park J, et al. Role of oncogenic K-Ras in cancer stem cell activation by aberrant Wnt/beta-catenin signaling. J Natl Cancer Inst. 2014;106:djt373.PubMedCrossRef
32.
Okada M, Shibuya K, Sato A, et al. Targeting the K-Ras–JNK axis eliminates cancer stem-like cells and prevents pancreatic tumor formation. Oncotarget. 2014;5:5100–12.PubMedPubMedCentralCrossRef
33.
Yuan XH, Yang J, Wang XY, et al. Association between EGFR/KRAS mutation and expression of VEGFA, VEGFR and VEGFR2 in lung adenocarcinoma. Oncol Lett. 2018;16:2105–12.PubMedPubMedCentral
34.
Takahashi O, Komaki R, Smith PD, et al. Combined MEK and VEGFR inhibition in orthotopic human lung cancer models results in enhanced inhibition of tumor angiogenesis, growth, and metastasis. Clin Cancer Res. 2012;18:1641–54.PubMedPubMedCentralCrossRef
35.
Coley AB, Ward A, Keeton AB, et al. Pan-RAS inhibitors: hitting multiple RAS isozymes with one stone. Adv Cancer Res. 2022;153:131–68.PubMedCrossRef
36.
Sennino B, Ishiguro-Oonuma T, Wei Y, et al. Suppression of tumor invasion and metastasis by concurrent inhibition of c-Met and VEGF signaling in pancreatic neuroendocrine tumors. Cancer Discov. 2012;2:270–87.PubMedPubMedCentralCrossRef
37.
Majeti BK, Lee JH, Simmons BH, Shojaei F. VEGF is an important mediator of tumor angiogenesis in malignant lesions in a genetically engineered mouse model of lung adenocarcinoma. BMC Cancer. 2013;13:213.PubMedPubMedCentralCrossRef
38.
Shibuya M. Vascular Endothelial Growth Factor (VEGF) and its receptor (VEGFR) signaling in angiogenesis: a crucial target for anti- and pro-angiogenic therapies. Genes Cancer. 2011;2:1097–105.PubMedPubMedCentralCrossRef
39.
Lv X, Li J, Zhang C, et al. The role of hypoxia-inducible factors in tumor angiogenesis and cell metabolism. Genes Dis. 2017;4:19–24.PubMedCrossRef
40.
41.
Zhao Y, Adjei AA. The clinical development of MEK inhibitors. Nat Rev Clin Oncol. 2014;11:385–400.PubMedCrossRef
42.
Conroy M, Cowzer D, Kolch W, Duffy AG. Emerging RAS-directed therapies for cancer. Cancer Drug Resist. 2021;4:543–58.PubMedPubMedCentral
43.
Metadata
Title
RETRACTED ARTICLE: KRAS activation in gastric cancer stem-like cells promotes tumor angiogenesis and metastasis
Authors
Changhwan Yoon
Jun Lu
Yukyung Jun
Yun-Suhk Suh
Bang-Jin Kim
Jacob E. Till
Jong Hyun Kim
Sara H. Keshavjee
Sandra Ryeom
Sam S. Yoon
Publication date
01-12-2023
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2023
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-023-11170-0

Other articles of this Issue 1/2023

BMC Cancer 1/2023 Go to the issue

Research

Correlation of clinicopathological and prognostic characteristics between endometriosis-associated and primary ovarian cancer

Research

circFNDC3B promotes esophageal squamous cell carcinoma progression by targeting MYO5A via miR-370-3p/miR-136-5p

Research

Development of an integrated predictive model for postoperative glioma-related epilepsy using gene-signature and clinical data

Research

Assessments of dietary intake and polygenic risk score in associations with colorectal cancer risk: evidence from the UK Biobank

Research

Dyslipidemia is associated with a poor prognosis of breast cancer in patients receiving neoadjuvant chemotherapy

Research

YTHDF3as a prognostic predictive biomarker of thyroid cancer and its correlation with immune infiltration
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits