Document Detail


Butyrate-rich colonic microenvironment is a relevant selection factor for metabolically adapted tumor cells.
MedLine Citation:
PMID:  20926374     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The short chain fatty acid (SCFA) butyrate is a product of colonic fermentation of dietary fibers. It is the main source of energy for normal colonocytes, but cannot be metabolized by most tumor cells. Butyrate also functions as a histone deacetylase (HDAC) inhibitor to control cell proliferation and apoptosis. In consequence, butyrate and its derived drugs are used in cancer therapy. Here we show that aggressive tumor cells that retain the capacity of metabolizing butyrate are positively selected in their microenvironment. In the mouse xenograft model, butyrate-preselected human colon cancer cells gave rise to subcutaneous tumors that grew faster and were more angiogenic than those derived from untreated cells. Similarly, butyrate-preselected cells demonstrated a significant increase in rates of homing to the lung after intravenous injection. Our data showed that butyrate regulates the expression of VEGF and its receptor KDR at the transcriptional level potentially through FoxM1, resulting in the generation of a functional VEGF:KDR autocrine growth loop. Cells selected by chronic exposure to butyrate express higher levels of MMP2, MMP9, α2 and α3 integrins, and lower levels of E-cadherin, a marker for epithelial to mesenchymal transition. The orthotopic model of colon cancer showed that cells preselected by butyrate are able to colonize the animals locally and at distant organs, whereas control cells can only generate a local tumor in the cecum. Together our data shows that a butyrate-rich microenvironment may select for tumor cells that are able to metabolize butyrate, which are also phenotypically more aggressive.
Authors:
Jacinta Serpa; Francisco Caiado; Tânia Carvalho; Cheila Torre; Luís G Gonçalves; Cristina Casalou; Pedro Lamosa; Margarida Rodrigues; Zhenping Zhu; Eric W F Lam; Sérgio Dias
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-10-06
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  285     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2010 Dec 
Date Detail:
Created Date:  2010-12-06     Completed Date:  2011-01-10     Revised Date:  2013-07-03    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  39211-23     Citation Subset:  IM    
Affiliation:
Angiogenesis Group, Instituto Português de Oncologia de Francisco Gentil, Centro de Lisboa, EPE (CIPM/IPOLFG), Lisbon 1099-023, Portugal.
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MeSH Terms
Descriptor/Qualifier:
Animals
Butyrates / pharmacology*
Cell Line, Tumor
Colon / metabolism*
Fatty Acids / chemistry
Gene Expression Regulation, Neoplastic*
Histone Deacetylases / metabolism
Humans
Intercellular Signaling Peptides and Proteins / metabolism
Mice
Mice, Inbred BALB C
Mice, SCID
Neoplasm Metastasis
Neoplasm Transplantation
Neoplasms / metabolism*
Vascular Endothelial Growth Factor A / metabolism
Chemical
Reg. No./Substance:
0/Butyrates; 0/Fatty Acids; 0/Intercellular Signaling Peptides and Proteins; 0/Vascular Endothelial Growth Factor A; EC 3.5.1.98/Histone Deacetylases
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