The Stemness-High Human Colorectal Cancer Cells Promote Angiogenesis by Producing Higher Amounts of Angiogenic Cytokines via Activation of the Egfr/Akt/Nf-κB Pathway.

Abstract

PURPOSE:

Cancer stem cells (CSCs) are responsible for cancer metastasis by stimulating tumor angiogenesis via various mechanisms. To elucidate the potential of the stemness-high human colorectal cancer (CRC) cells (i.e., CRCSCs) in activating angiogenesis, effects of the GATA6-overexpressing HCT-116 and HT-29 human CRC clones established previously by us in promoting the angiogenesis of human umbilical vein endothelial cells (HUVECs) were examined.

METHODS:

Angiogenesis-promoting effects (i.e., migration, invasion, DNA synthesis, and tube formation) in HUVECs of the conditioned media (CM) from various human CRC clones were analyzed. MMP activities were assessed using a zymography assay. Western blotting and selective inhibitors were used to dissect the signaling pathway involved. IHC was used to examine the vascular density in tumor xenografts.

RESULTS:

We found that the conditioned media (CM) collected from the GATA6-overexpressing clones enhanced angiogenesis of HUVECs more effectively which might be attributed partly to a higher MMP-9 production by HUVECs. Subsequently, elevated levels of IL-8 and VEGF-A were detected in the CM whose tube formation-enhancing activities were abolished by the co-treatment with either a VEGFR2 inhibitor or an IL-8 neutralizing antibody. Interestingly, increased production of these cytokines in the GATA6-overexpressing clones was due to an EGFR/AKT-mediated activation of NF-κB. Furthermore, not only were the levels of CD31 and endomucin but also the blood vessel density was much higher in the xenograft tumors grown from these clones.

CONCLUSION:

Our findings demonstrate that human CRCSCs promote a stronger angiogenesis by producing higher amounts of angiogenic factors through activation of the EGFR/AKT/NF-κB pathway.

• Authors: Shin-Yi Chung, Ta-Chung Chao, Yeu Su
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 22 Issue 3 (Jan 29 2021) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 33573006 (Publication Type: Journal Article)

Chemical References

• Cytokines
• GATA6 Transcription Factor
• GATA6 protein, human
• NF-kappa B
• EGFR protein, human
• ErbB Receptors
• Proto-Oncogene Proteins c-akt

Topics

• Cell Movement
• Colorectal Neoplasms (metabolism, pathology)
• Cytokines (metabolism)
• ErbB Receptors (metabolism)
• GATA6 Transcription Factor (metabolism)
• HCT116 Cells
• HT29 Cells
• Human Umbilical Vein Endothelial Cells
• Humans
• NF-kappa B (metabolism)
• Neoplastic Stem Cells (metabolism, pathology)
• Neovascularization, Pathologic (metabolism, pathology)
• Proto-Oncogene Proteins c-akt (metabolism)
• Signal Transduction