BACKGROUND & AIMS: Colorectal cancer is a complex disease involving immune defense mechanisms within the tumor. Herein, we used data integration and biomolecular network reconstruction to generate hypotheses about the mechanisms underlying immune responses in colorectal cancer that are relevant to tumor recurrence. METHODS: Mechanistic hypotheses were formulated on the basis of data from 108 patients and tested using different assays (gene expression, phenome mapping, tissue-microarrays, T-cell receptor [TCR] repertoire). RESULTS: This integrative approach revealed that chemoattraction and adhesion play important roles in determining the density of intratumoral immune cells. The presence of specific chemokines (CX3CL1, CXCL10, CXCL9) and adhesion molecules (ICAM1, VCAM1, MADCAM1) correlated with different subsets of immune cells and with high densities of T-cell subpopulations within specific tumor regions. High expression of these molecules correlated with prolonged disease-free survival. Moreover, the expression of certain chemokines associated with particular TCR repertoire and specific TCR use predicted patient survival. CONCLUSIONS: Data integration and biomolecular network reconstruction is a powerful approach to uncover molecular mechanisms. This study shows the utility of this approach for the investigation of malignant tumors and other diseases. In colorectal cancer, the expression of specific chemokines and adhesion molecules were found as being critical for high densities of T-cell subsets within the tumor and associated with particular TCR repertoire. Intratumoral-specific TCR use correlated with the prognosis of the patients. 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.
BACKGROUND & AIMS:Colorectal cancer is a complex disease involving immune defense mechanisms within the tumor. Herein, we used data integration and biomolecular network reconstruction to generate hypotheses about the mechanisms underlying immune responses in colorectal cancer that are relevant to tumor recurrence. METHODS: Mechanistic hypotheses were formulated on the basis of data from 108 patients and tested using different assays (gene expression, phenome mapping, tissue-microarrays, T-cell receptor [TCR] repertoire). RESULTS: This integrative approach revealed that chemoattraction and adhesion play important roles in determining the density of intratumoral immune cells. The presence of specific chemokines (CX3CL1, CXCL10, CXCL9) and adhesion molecules (ICAM1, VCAM1, MADCAM1) correlated with different subsets of immune cells and with high densities of T-cell subpopulations within specific tumor regions. High expression of these molecules correlated with prolonged disease-free survival. Moreover, the expression of certain chemokines associated with particular TCR repertoire and specific TCR use predicted patient survival. CONCLUSIONS: Data integration and biomolecular network reconstruction is a powerful approach to uncover molecular mechanisms. This study shows the utility of this approach for the investigation of malignant tumors and other diseases. In colorectal cancer, the expression of specific chemokines and adhesion molecules were found as being critical for high densities of T-cell subsets within the tumor and associated with particular TCR repertoire. Intratumoral-specific TCR use correlated with the prognosis of the patients. 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.
Authors: Robert E White; Patrick C Rämer; Kikkeri N Naresh; Sonja Meixlsperger; Laurie Pinaud; Cliona Rooney; Barbara Savoldo; Rita Coutinho; Csaba Bödör; John Gribben; Hazem A Ibrahim; Mark Bower; Jamie P Nourse; Maher K Gandhi; Jaap Middeldorp; Fathima Z Cader; Paul Murray; Christian Münz; Martin J Allday Journal: J Clin Invest Date: 2012-03-12 Impact factor: 14.808
Authors: A Jafarzadeh; H Fooladseresht; K Minaee; M R Bazrafshani; A Khosravimashizi; M Nemati; M Mohammadizadeh; M M Mohammadi; A Ghaderi Journal: Tumour Biol Date: 2014-10-22
Authors: Ravikumar Muthuswamy; Erik Berk; Beth Fallert Junecko; Herbert J Zeh; Amer H Zureikat; Daniel Normolle; The Minh Luong; Todd A Reinhart; David L Bartlett; Pawel Kalinski Journal: Cancer Res Date: 2012-05-16 Impact factor: 12.701