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Anti-VEGF treatment-resistant pancreatic cancers secrete proinflammatory factors that contribute to malignant progression by inducing an EMT cell phenotype.

Publication ,  Journal Article
Carbone, C; Moccia, T; Zhu, C; Paradiso, G; Budillon, A; Chiao, PJ; Abbruzzese, JL; Melisi, D
Published in: Clin Cancer Res
September 1, 2011

PURPOSE: The resistance of tumors to antiangiogenic therapies is becoming increasingly relevant. There are currently no validated predictive biomarkers for selecting which cancer patients will benefit from antiangiogenic therapy. Also lacking are resistance biomarkers that can identify which escape pathways should be targeted after tumors develop resistance to VEGF treatment. Recent studies showed that anti-VEGF treatment can make tumor cells more aggressive and metastatic. However, the mechanisms and mediators of this are unidentified. Therefore, we aimed this study at directly identifying the tumor cell-initiated mechanisms responsible for the resistance of pancreatic cancer to anti-VEGF treatment. EXPERIMENTAL DESIGN: We established and validated two murine models of human pancreatic cancer resistant to the VEGF-specific antibody bevacizumab in vivo. We used a genome-wide analysis to directly identify which tumor-secreted factors were overexpressed by pancreatic cancer cells that were resistant to anti-VEGF treatment. RESULTS: Rather than direct proangiogenic factors, we identified several proinflammatory factors that were expressed at higher levels in cells resistant to anti-VEGF treatment than in treatment-sensitive control cells. These proinflammatory factors acted in a paracrine manner to stimulate the recruitment of CD11b(+) proangiogenic myeloid cells. Also, we found that secreted factors overexpressed by anti-VEGF treatment-resistant pancreatic cancer cells acted in an autocrine manner to induce epithelial-to-mesenchymal transition (EMT) and were thus responsible for increased aggressiveness of bevacizumab-resistant pancreatic tumors. CONCLUSIONS: Our results identified proinflammatory factors and EMT markers as potential biomarkers for selecting patients with pancreatic cancer for antiangiogenic therapy.

Duke Scholars

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Published In

Clin Cancer Res

DOI

EISSN

1557-3265

Publication Date

September 1, 2011

Volume

17

Issue

17

Start / End Page

5822 / 5832

Location

United States

Related Subject Headings

  • Vascular Endothelial Growth Factor A
  • Tumor Escape
  • Transplantation, Heterologous
  • Pancreatic Neoplasms
  • Oncology & Carcinogenesis
  • Oligonucleotide Array Sequence Analysis
  • Mice, Nude
  • Mice
  • Humans
  • Genome-Wide Association Study
 

Citation

APA
Chicago
ICMJE
MLA
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Carbone, C., Moccia, T., Zhu, C., Paradiso, G., Budillon, A., Chiao, P. J., … Melisi, D. (2011). Anti-VEGF treatment-resistant pancreatic cancers secrete proinflammatory factors that contribute to malignant progression by inducing an EMT cell phenotype. Clin Cancer Res, 17(17), 5822–5832. https://doi.org/10.1158/1078-0432.CCR-11-1185
Carbone, Carmine, Tania Moccia, Cihui Zhu, Genni Paradiso, Alfredo Budillon, Paul J. Chiao, James L. Abbruzzese, and Davide Melisi. “Anti-VEGF treatment-resistant pancreatic cancers secrete proinflammatory factors that contribute to malignant progression by inducing an EMT cell phenotype.Clin Cancer Res 17, no. 17 (September 1, 2011): 5822–32. https://doi.org/10.1158/1078-0432.CCR-11-1185.
Carbone C, Moccia T, Zhu C, Paradiso G, Budillon A, Chiao PJ, et al. Anti-VEGF treatment-resistant pancreatic cancers secrete proinflammatory factors that contribute to malignant progression by inducing an EMT cell phenotype. Clin Cancer Res. 2011 Sep 1;17(17):5822–32.
Carbone, Carmine, et al. “Anti-VEGF treatment-resistant pancreatic cancers secrete proinflammatory factors that contribute to malignant progression by inducing an EMT cell phenotype.Clin Cancer Res, vol. 17, no. 17, Sept. 2011, pp. 5822–32. Pubmed, doi:10.1158/1078-0432.CCR-11-1185.
Carbone C, Moccia T, Zhu C, Paradiso G, Budillon A, Chiao PJ, Abbruzzese JL, Melisi D. Anti-VEGF treatment-resistant pancreatic cancers secrete proinflammatory factors that contribute to malignant progression by inducing an EMT cell phenotype. Clin Cancer Res. 2011 Sep 1;17(17):5822–5832.

Published In

Clin Cancer Res

DOI

EISSN

1557-3265

Publication Date

September 1, 2011

Volume

17

Issue

17

Start / End Page

5822 / 5832

Location

United States

Related Subject Headings

  • Vascular Endothelial Growth Factor A
  • Tumor Escape
  • Transplantation, Heterologous
  • Pancreatic Neoplasms
  • Oncology & Carcinogenesis
  • Oligonucleotide Array Sequence Analysis
  • Mice, Nude
  • Mice
  • Humans
  • Genome-Wide Association Study