Distinctive responsiveness to stromal signaling accompanies histologic grade programming of cancer cells

Maria Gloria Luciani, Junhee Seok, Aejaz Sayeed, Stacey Champion, William H. Goodson, Stefanie S. Jeffrey, Wenzhong Xiao, Michael Mindrinos, Ronald W. Davis, Shanaz H. Dairkee

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article numbere20016
JournalPLoS One
Volume6
Issue number5
DOIs
Publication statusPublished - 2011 May 25
Externally publishedYes

Fingerprint

Tumors
Cells
neoplasms
Fibroblasts
Neoplasms
fibroblasts
Gene expression
Crosstalk
Genes
gene expression
Gene Expression
neoplasm cells
Scavenging
Cell proliferation
genes
Cell death
relapse
Tumor Microenvironment
endpoints
Case Management

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Luciani, M. G., Seok, J., Sayeed, A., Champion, S., Goodson, W. H., Jeffrey, S. S., ... Dairkee, S. H. (2011). Distinctive responsiveness to stromal signaling accompanies histologic grade programming of cancer cells. PLoS One, 6(5), [e20016]. https://doi.org/10.1371/journal.pone.0020016

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.

In: PLoS One, Vol. 6, No. 5, e20016, 25.05.2011.

Research output: Contribution to journalArticle

Luciani, MG, Seok, J, Sayeed, A, Champion, S, Goodson, WH, Jeffrey, SS, Xiao, W, Mindrinos, M, Davis, RW & Dairkee, SH 2011, 'Distinctive responsiveness to stromal signaling accompanies histologic grade programming of cancer cells', PLoS One, vol. 6, no. 5, e20016. https://doi.org/10.1371/journal.pone.0020016
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. In: PLoS One. 2011 ; Vol. 6, No. 5.
@article{fccc504f70894e7c87f8a1203d4874a0,
title = "Distinctive responsiveness to stromal signaling accompanies histologic grade programming of cancer cells",
abstract = "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.",
author = "Luciani, {Maria Gloria} and Junhee Seok and Aejaz Sayeed and Stacey Champion and Goodson, {William H.} and Jeffrey, {Stefanie S.} and Wenzhong Xiao and Michael Mindrinos and Davis, {Ronald W.} and Dairkee, {Shanaz H.}",
year = "2011",
month = "5",
day = "25",
doi = "10.1371/journal.pone.0020016",
language = "English",
volume = "6",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "5",

}

TY - JOUR

T1 - Distinctive responsiveness to stromal signaling accompanies histologic grade programming of cancer cells

AU - Luciani, Maria Gloria

AU - Seok, Junhee

AU - Sayeed, Aejaz

AU - Champion, Stacey

AU - Goodson, William H.

AU - Jeffrey, Stefanie S.

AU - Xiao, Wenzhong

AU - Mindrinos, Michael

AU - Davis, Ronald W.

AU - Dairkee, Shanaz H.

PY - 2011/5/25

Y1 - 2011/5/25

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=79956282369&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79956282369&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0020016

DO - 10.1371/journal.pone.0020016

M3 - Article

VL - 6

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 5

M1 - e20016

ER -