Immune-dependent and independent antitumor activity of GM-CSF aberrantly expressed by mouse and human colorectal tumors.

Abstract

Granulocyte-macrophage colony-stimulating factor (GM-CSF/CSF2) is a cytokine produced in the hematologic compartment that may enhance antitumor immune responses, mainly by activation of dendritic cells. Here, we show that more than one-third of human colorectal tumors exhibit aberrant DNA demethylation of the GM-CSF promoter and overexpress the cytokine. Mouse engraftment experiments with autologous and homologous colon tumors engineered to repress the ectopic secretion of GM-CSF revealed the tumor-secreted GM-CSF to have an immune-associated antitumor effect. Unexpectedly, an immune-independent antitumor effect was observed that depended on the ectopic expression of GM-CSF receptor subunits by tumors. Cancer cells expressing GM-CSF and its receptor did not develop into tumors when autografted into immunocompetent mice. Similarly, 100% of the patients with human colon tumors that overexpressed GM-CSF and its receptor subunits survived at least 5 years after diagnosis. These data suggest that expression of GM-CSF and its receptor subunits by colon tumors may be a useful marker for prognosis as well as for patient stratification in cancer immunotherapy.

• Authors: Rocio G Urdinguio, Agustin F Fernandez, Angela Moncada-Pazos, Covadonga Huidobro, Ramon M Rodriguez, Cecilia Ferrero, Pablo Martinez-Camblor, Alvaro J Obaya, Teresa Bernal, Adolfo Parra-Blanco, Luis Rodrigo, Maria Santacana, Xavier Matias-Guiu, Beatriz Soldevilla, Gemma Dominguez, Felix Bonilla, Santiago Cal, Carlos Lopez-Otin, Mario F Fraga
• Journal: Cancer research (Cancer Res) Vol. 73 Issue 1 Pg. 395-405 (Jan 01 2013) ISSN: 1538-7445 [Electronic] United States
• PMID: 23108143 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers, Tumor
• Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
• Granulocyte-Macrophage Colony-Stimulating Factor

Topics

• Animals
• Biomarkers, Tumor
• Colorectal Neoplasms (genetics, immunology, metabolism)
• DNA Methylation
• Enzyme-Linked Immunosorbent Assay
• Granulocyte-Macrophage Colony-Stimulating Factor (biosynthesis, genetics, immunology)
• Humans
• Immunohistochemistry
• In Situ Hybridization
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Nude
• Prognosis
• Promoter Regions, Genetic
• Real-Time Polymerase Chain Reaction
• Receptors, Granulocyte-Macrophage Colony-Stimulating Factor (biosynthesis)
• Tissue Array Analysis
• Transfection