Duel nature of TGF-β signaling: Tumor suppressor vs. tumor promoter

Kurtis E. Bachman, Ben Ho Park

Research output: Contribution to journalArticle

Abstract

Purpose of review: Transforming growth factor β type I (TGF-β) is a ubiquitous cytokine that is well known for its ability to inhibit epithelial cell proliferation. Somatic mutations abrogating the TGF-β signal transduction pathway are found in many gastrointestinal cancers, confirming its importance as a tumor suppressor. In contrast, many nongastrointestinal epithelial malignancies lack these somatic alterations, yet these cancers still acquire resistance to the growth-inhibitory effects of TGF-β. In many instances, this resistance is part of a signaling switch whereby TGF-β loses its growth inhibitory effects and is then used by the epithelial cell in a growth-promoting fashion. The mechanisms that underlie this change in the phenotypic growth response to TGF-β are now being elucidated. This review focuses on recent advances in understanding the dual nature of the TGF-β pathway as it relates to human carcinogenesis. Recent findings: Elucidating the molecular basis that enables epithelial cells to change from a growth-suppressive to growth-stimulatory phenotype on TGF-β exposure is an area of active research. Besides enhancing cancer cell growth, TGF-β is also thought to promote a malignant cell's ability to metastasize by mediating changes in the cytoskeletal architecture, known as an epithelial-to-mesenchymal transition. This process enables a cancer cell to invade and spread to distal sites. Strong evidence has now emerged suggesting that the ability of a cell to use TGF-β as a growth-promoting/invasive cytokine is a result of a number of different cellular and nuclear factors, including the absence or disruption of cyclin-dependent kinase inhibitors. This imbalance in cell cycle regulators may be the key element that dictates a cell's response to TGF-β as growth-inhibitory versus growth-stimulatory, thus explaining the dual nature of TGF-β signaling. Summary: Current studies are beginning to shed light on the mechanisms that allow some nongastrointestinal epithelial cancers to evade the growth inhibitory effects of TGF-β while simultaneously using this cytokine for growth advantage. By dissecting this phenotypic switch during tumor development, important genes, proteins, and pathways that are involved with TGF-β signaling continue to be discovered. Knowledge of how premalignant cells and tumor celts respond to the growth promoting effects of TGF-β and the genes that regulate this process will aid in the development of novel therapeutics and treatment strategies.

Original languageEnglish (US)
Pages (from-to)49-54
Number of pages6
JournalCurrent Opinion in Oncology
Volume17
Issue number1
DOIs
StatePublished - Jan 2005

Fingerprint

Carcinogens
Growth
Neoplasms
Epithelial Cells
Cytokines
Gastrointestinal Neoplasms
Epithelial-Mesenchymal Transition
Cyclin-Dependent Kinases
Transforming Growth Factors
Signal Transduction
Cell Cycle
Carcinogenesis
Cell Proliferation
Phenotype

Keywords

  • Cancer
  • p21
  • Smad
  • TGF-β

ASJC Scopus subject areas

  • Cancer Research

Cite this

Duel nature of TGF-β signaling : Tumor suppressor vs. tumor promoter. / Bachman, Kurtis E.; Park, Ben Ho.

In: Current Opinion in Oncology, Vol. 17, No. 1, 01.2005, p. 49-54.

Research output: Contribution to journalArticle

Bachman, Kurtis E. ; Park, Ben Ho. / Duel nature of TGF-β signaling : Tumor suppressor vs. tumor promoter. In: Current Opinion in Oncology. 2005 ; Vol. 17, No. 1. pp. 49-54.
@article{338fe594f9d54b99a8df1e1f38e9094e,
title = "Duel nature of TGF-β signaling: Tumor suppressor vs. tumor promoter",
abstract = "Purpose of review: Transforming growth factor β type I (TGF-β) is a ubiquitous cytokine that is well known for its ability to inhibit epithelial cell proliferation. Somatic mutations abrogating the TGF-β signal transduction pathway are found in many gastrointestinal cancers, confirming its importance as a tumor suppressor. In contrast, many nongastrointestinal epithelial malignancies lack these somatic alterations, yet these cancers still acquire resistance to the growth-inhibitory effects of TGF-β. In many instances, this resistance is part of a signaling switch whereby TGF-β loses its growth inhibitory effects and is then used by the epithelial cell in a growth-promoting fashion. The mechanisms that underlie this change in the phenotypic growth response to TGF-β are now being elucidated. This review focuses on recent advances in understanding the dual nature of the TGF-β pathway as it relates to human carcinogenesis. Recent findings: Elucidating the molecular basis that enables epithelial cells to change from a growth-suppressive to growth-stimulatory phenotype on TGF-β exposure is an area of active research. Besides enhancing cancer cell growth, TGF-β is also thought to promote a malignant cell's ability to metastasize by mediating changes in the cytoskeletal architecture, known as an epithelial-to-mesenchymal transition. This process enables a cancer cell to invade and spread to distal sites. Strong evidence has now emerged suggesting that the ability of a cell to use TGF-β as a growth-promoting/invasive cytokine is a result of a number of different cellular and nuclear factors, including the absence or disruption of cyclin-dependent kinase inhibitors. This imbalance in cell cycle regulators may be the key element that dictates a cell's response to TGF-β as growth-inhibitory versus growth-stimulatory, thus explaining the dual nature of TGF-β signaling. Summary: Current studies are beginning to shed light on the mechanisms that allow some nongastrointestinal epithelial cancers to evade the growth inhibitory effects of TGF-β while simultaneously using this cytokine for growth advantage. By dissecting this phenotypic switch during tumor development, important genes, proteins, and pathways that are involved with TGF-β signaling continue to be discovered. Knowledge of how premalignant cells and tumor celts respond to the growth promoting effects of TGF-β and the genes that regulate this process will aid in the development of novel therapeutics and treatment strategies.",
keywords = "Cancer, p21, Smad, TGF-β",
author = "Bachman, {Kurtis E.} and Park, {Ben Ho}",
year = "2005",
month = "1",
doi = "10.1097/01.cco.0000143682.45316.ae",
language = "English (US)",
volume = "17",
pages = "49--54",
journal = "Current Opinion in Oncology",
issn = "1040-8746",
publisher = "Lippincott Williams and Wilkins",
number = "1",

}

TY - JOUR

T1 - Duel nature of TGF-β signaling

T2 - Tumor suppressor vs. tumor promoter

AU - Bachman, Kurtis E.

AU - Park, Ben Ho

PY - 2005/1

Y1 - 2005/1

N2 - Purpose of review: Transforming growth factor β type I (TGF-β) is a ubiquitous cytokine that is well known for its ability to inhibit epithelial cell proliferation. Somatic mutations abrogating the TGF-β signal transduction pathway are found in many gastrointestinal cancers, confirming its importance as a tumor suppressor. In contrast, many nongastrointestinal epithelial malignancies lack these somatic alterations, yet these cancers still acquire resistance to the growth-inhibitory effects of TGF-β. In many instances, this resistance is part of a signaling switch whereby TGF-β loses its growth inhibitory effects and is then used by the epithelial cell in a growth-promoting fashion. The mechanisms that underlie this change in the phenotypic growth response to TGF-β are now being elucidated. This review focuses on recent advances in understanding the dual nature of the TGF-β pathway as it relates to human carcinogenesis. Recent findings: Elucidating the molecular basis that enables epithelial cells to change from a growth-suppressive to growth-stimulatory phenotype on TGF-β exposure is an area of active research. Besides enhancing cancer cell growth, TGF-β is also thought to promote a malignant cell's ability to metastasize by mediating changes in the cytoskeletal architecture, known as an epithelial-to-mesenchymal transition. This process enables a cancer cell to invade and spread to distal sites. Strong evidence has now emerged suggesting that the ability of a cell to use TGF-β as a growth-promoting/invasive cytokine is a result of a number of different cellular and nuclear factors, including the absence or disruption of cyclin-dependent kinase inhibitors. This imbalance in cell cycle regulators may be the key element that dictates a cell's response to TGF-β as growth-inhibitory versus growth-stimulatory, thus explaining the dual nature of TGF-β signaling. Summary: Current studies are beginning to shed light on the mechanisms that allow some nongastrointestinal epithelial cancers to evade the growth inhibitory effects of TGF-β while simultaneously using this cytokine for growth advantage. By dissecting this phenotypic switch during tumor development, important genes, proteins, and pathways that are involved with TGF-β signaling continue to be discovered. Knowledge of how premalignant cells and tumor celts respond to the growth promoting effects of TGF-β and the genes that regulate this process will aid in the development of novel therapeutics and treatment strategies.

AB - Purpose of review: Transforming growth factor β type I (TGF-β) is a ubiquitous cytokine that is well known for its ability to inhibit epithelial cell proliferation. Somatic mutations abrogating the TGF-β signal transduction pathway are found in many gastrointestinal cancers, confirming its importance as a tumor suppressor. In contrast, many nongastrointestinal epithelial malignancies lack these somatic alterations, yet these cancers still acquire resistance to the growth-inhibitory effects of TGF-β. In many instances, this resistance is part of a signaling switch whereby TGF-β loses its growth inhibitory effects and is then used by the epithelial cell in a growth-promoting fashion. The mechanisms that underlie this change in the phenotypic growth response to TGF-β are now being elucidated. This review focuses on recent advances in understanding the dual nature of the TGF-β pathway as it relates to human carcinogenesis. Recent findings: Elucidating the molecular basis that enables epithelial cells to change from a growth-suppressive to growth-stimulatory phenotype on TGF-β exposure is an area of active research. Besides enhancing cancer cell growth, TGF-β is also thought to promote a malignant cell's ability to metastasize by mediating changes in the cytoskeletal architecture, known as an epithelial-to-mesenchymal transition. This process enables a cancer cell to invade and spread to distal sites. Strong evidence has now emerged suggesting that the ability of a cell to use TGF-β as a growth-promoting/invasive cytokine is a result of a number of different cellular and nuclear factors, including the absence or disruption of cyclin-dependent kinase inhibitors. This imbalance in cell cycle regulators may be the key element that dictates a cell's response to TGF-β as growth-inhibitory versus growth-stimulatory, thus explaining the dual nature of TGF-β signaling. Summary: Current studies are beginning to shed light on the mechanisms that allow some nongastrointestinal epithelial cancers to evade the growth inhibitory effects of TGF-β while simultaneously using this cytokine for growth advantage. By dissecting this phenotypic switch during tumor development, important genes, proteins, and pathways that are involved with TGF-β signaling continue to be discovered. Knowledge of how premalignant cells and tumor celts respond to the growth promoting effects of TGF-β and the genes that regulate this process will aid in the development of novel therapeutics and treatment strategies.

KW - Cancer

KW - p21

KW - Smad

KW - TGF-β

UR - http://www.scopus.com/inward/record.url?scp=13144281709&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=13144281709&partnerID=8YFLogxK

U2 - 10.1097/01.cco.0000143682.45316.ae

DO - 10.1097/01.cco.0000143682.45316.ae

M3 - Article

C2 - 15608513

AN - SCOPUS:13144281709

VL - 17

SP - 49

EP - 54

JO - Current Opinion in Oncology

JF - Current Opinion in Oncology

SN - 1040-8746

IS - 1

ER -