Cargando…
Distinctive Responsiveness to Stromal Signaling Accompanies Histologic Grade Programming of Cancer Cells
Whether stromal components facilitate growth, invasion, and dissemination of cancer cells or suppress neoplastic lesions from further malignant progression is a continuing conundrum in tumor biology. Conceptualizing a dynamic picture of tumorigenesis is complicated by inter-individual heterogeneity....
Autores principales: | , , , , , , , , , |
---|---|
Formato: | Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2011
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3098270/ https://www.ncbi.nlm.nih.gov/pubmed/21625507 http://dx.doi.org/10.1371/journal.pone.0020016 |
_version_ | 1782203951277408256 |
---|---|
author | Luciani, Maria Gloria Seok, Junhee Sayeed, Aejaz Champion, Stacey Goodson, William H. Jeffrey, Stefanie S. Xiao, Wenzhong Mindrinos, Michael Davis, Ronald W. Dairkee, Shanaz H. |
author_facet | Luciani, Maria Gloria Seok, Junhee Sayeed, Aejaz Champion, Stacey Goodson, William H. Jeffrey, Stefanie S. Xiao, Wenzhong Mindrinos, Michael Davis, Ronald W. Dairkee, Shanaz H. |
author_sort | Luciani, Maria Gloria |
collection | PubMed |
description | Whether stromal components facilitate growth, invasion, and dissemination of cancer cells or suppress neoplastic lesions from further malignant progression is a continuing conundrum in tumor biology. Conceptualizing a dynamic picture of tumorigenesis is complicated by inter-individual heterogeneity. In the post genomic era, unraveling such complexity remains a challenge for the cancer biologist. Towards establishing a functional association between cellular crosstalk and differential cancer aggressiveness, we identified a signature of malignant breast epithelial response to stromal signaling. Proximity to fibroblasts resulted in gene transcript alterations of >2-fold for 107 probes, collectively designated as Fibroblast Triggered Gene Expression in Tumor (FTExT). The hazard ratio predicted by the FTExT classifier for distant relapse in patients with intermediate and high grade breast tumors was significant compared to routine clinical variables (dataset 1, n = 258, HR – 2.11, 95% CI 1.17–3.80, p-value 0.01; dataset 2, n = 171, HR - 3.07, 95% CI 1.21–7.83, p-value 0.01). Biofunctions represented by FTExT included inflammatory signaling, free radical scavenging, cell death, and cell proliferation. Unlike genes of the ‘proliferation cluster’, which are overexpressed in aggressive primary tumors, FTExT genes were uniquely repressed in such cases. As proof of concept for our correlative findings, which link stromal-epithelial crosstalk and tumor behavior, we show a distinctive differential in stromal impact on prognosis-defining functional endpoints of cell cycle progression, and resistance to therapy-induced growth arrest and apoptosis in low vs. high grade cancer cells. Our experimental data thus reveal aspects of ‘paracrine cooperativity’ that are exclusively contingent upon the histopathologically defined grade of interacting tumor epithelium, and demonstrate that epithelial responsiveness to the tumor microenvironment is a deterministic factor underlying clinical outcome. In this light, early attenuation of epithelial-stromal crosstalk could improve the management of cases prone to be clinically challenging. |
format | Text |
id | pubmed-3098270 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-30982702011-05-27 Distinctive Responsiveness to Stromal Signaling Accompanies Histologic Grade Programming of Cancer Cells Luciani, Maria Gloria Seok, Junhee Sayeed, Aejaz Champion, Stacey Goodson, William H. Jeffrey, Stefanie S. Xiao, Wenzhong Mindrinos, Michael Davis, Ronald W. Dairkee, Shanaz H. PLoS One Research Article Whether stromal components facilitate growth, invasion, and dissemination of cancer cells or suppress neoplastic lesions from further malignant progression is a continuing conundrum in tumor biology. Conceptualizing a dynamic picture of tumorigenesis is complicated by inter-individual heterogeneity. In the post genomic era, unraveling such complexity remains a challenge for the cancer biologist. Towards establishing a functional association between cellular crosstalk and differential cancer aggressiveness, we identified a signature of malignant breast epithelial response to stromal signaling. Proximity to fibroblasts resulted in gene transcript alterations of >2-fold for 107 probes, collectively designated as Fibroblast Triggered Gene Expression in Tumor (FTExT). The hazard ratio predicted by the FTExT classifier for distant relapse in patients with intermediate and high grade breast tumors was significant compared to routine clinical variables (dataset 1, n = 258, HR – 2.11, 95% CI 1.17–3.80, p-value 0.01; dataset 2, n = 171, HR - 3.07, 95% CI 1.21–7.83, p-value 0.01). Biofunctions represented by FTExT included inflammatory signaling, free radical scavenging, cell death, and cell proliferation. Unlike genes of the ‘proliferation cluster’, which are overexpressed in aggressive primary tumors, FTExT genes were uniquely repressed in such cases. As proof of concept for our correlative findings, which link stromal-epithelial crosstalk and tumor behavior, we show a distinctive differential in stromal impact on prognosis-defining functional endpoints of cell cycle progression, and resistance to therapy-induced growth arrest and apoptosis in low vs. high grade cancer cells. Our experimental data thus reveal aspects of ‘paracrine cooperativity’ that are exclusively contingent upon the histopathologically defined grade of interacting tumor epithelium, and demonstrate that epithelial responsiveness to the tumor microenvironment is a deterministic factor underlying clinical outcome. In this light, early attenuation of epithelial-stromal crosstalk could improve the management of cases prone to be clinically challenging. Public Library of Science 2011-05-19 /pmc/articles/PMC3098270/ /pubmed/21625507 http://dx.doi.org/10.1371/journal.pone.0020016 Text en Luciani et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Luciani, Maria Gloria Seok, Junhee Sayeed, Aejaz Champion, Stacey Goodson, William H. Jeffrey, Stefanie S. Xiao, Wenzhong Mindrinos, Michael Davis, Ronald W. Dairkee, Shanaz H. Distinctive Responsiveness to Stromal Signaling Accompanies Histologic Grade Programming of Cancer Cells |
title | Distinctive Responsiveness to Stromal Signaling Accompanies Histologic Grade Programming of Cancer Cells |
title_full | Distinctive Responsiveness to Stromal Signaling Accompanies Histologic Grade Programming of Cancer Cells |
title_fullStr | Distinctive Responsiveness to Stromal Signaling Accompanies Histologic Grade Programming of Cancer Cells |
title_full_unstemmed | Distinctive Responsiveness to Stromal Signaling Accompanies Histologic Grade Programming of Cancer Cells |
title_short | Distinctive Responsiveness to Stromal Signaling Accompanies Histologic Grade Programming of Cancer Cells |
title_sort | distinctive responsiveness to stromal signaling accompanies histologic grade programming of cancer cells |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3098270/ https://www.ncbi.nlm.nih.gov/pubmed/21625507 http://dx.doi.org/10.1371/journal.pone.0020016 |
work_keys_str_mv | AT lucianimariagloria distinctiveresponsivenesstostromalsignalingaccompanieshistologicgradeprogrammingofcancercells AT seokjunhee distinctiveresponsivenesstostromalsignalingaccompanieshistologicgradeprogrammingofcancercells AT sayeedaejaz distinctiveresponsivenesstostromalsignalingaccompanieshistologicgradeprogrammingofcancercells AT championstacey distinctiveresponsivenesstostromalsignalingaccompanieshistologicgradeprogrammingofcancercells AT goodsonwilliamh distinctiveresponsivenesstostromalsignalingaccompanieshistologicgradeprogrammingofcancercells AT jeffreystefanies distinctiveresponsivenesstostromalsignalingaccompanieshistologicgradeprogrammingofcancercells AT xiaowenzhong distinctiveresponsivenesstostromalsignalingaccompanieshistologicgradeprogrammingofcancercells AT mindrinosmichael distinctiveresponsivenesstostromalsignalingaccompanieshistologicgradeprogrammingofcancercells AT davisronaldw distinctiveresponsivenesstostromalsignalingaccompanieshistologicgradeprogrammingofcancercells AT dairkeeshanazh distinctiveresponsivenesstostromalsignalingaccompanieshistologicgradeprogrammingofcancercells |