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Transforming growth factor beta and fibroblast growth factor as promoters of tumor progression to malignancy
J A Wright1, E A Turley, A H Greenberg
1Manitoba Institute of Cell Biology, Winnipeg, Canada.
Abstract:
Polypeptide growth factors are a diverse group of biological regulators. Because they are fundamentally involved in the cellular processes that are important for transformation and progression to malignancy, alterations in growth factor control and in their signal pathways are often observed in tumor cells. In this review, we consider the participation of growth factors and the mechanisms by which they effect tumor progression, using as examples members of the transforming growth factor beta (TGF-beta) and fibroblast growth factor (FGF) families. We explore the hypothesis that although abrogation of TGF-beta negative growth regulation is necessary for transformation, in the later stages of tumor progression, TGF-beta plays a direct role in the enhancement of invasion and metastasis as an autocrine stimulator of these processes. In addition, we present evidence that demonstrates both the potential and the importance of members of the FGF family in transformation and induction of metastasis. Several models of growth factor regulation of malignancy are presented in which we demonstrate (1) a link between TGF-beta 1 mitogenic stimulation of malignant cells and alterations in the expression of ribonucleotide reductase, a key rate-limiting step in the synthesis of DNA and in cell proliferation; (2) autocrine and/or intracrine FGF mitogenic stimulation of malignant cell proliferation and metastasis; and (3) autocrine TGF-beta regulation of malignant cell locomotion and invasion through elevated proteolytic activity and increased synthesis of hyaluronan and RHAMM, a novel hyaluronan cell surface receptor.
Insights
Growth factors like transforming growth factor beta (TGF-beta) and fibroblast growth factor (FGF) drive tumor progression. Aberrant TGF-beta signaling promotes invasion and metastasis in later cancer stages.
Area of Science:
- Molecular Biology
- Cancer Biology
- Cell Signaling
Background:
- Polypeptide growth factors regulate cellular processes crucial for cancer development.
- Tumor cells often exhibit altered growth factor signaling pathways.
- Transforming growth factor beta (TGF-beta) and fibroblast growth factor (FGF) families are key regulators.
Purpose of the Study:
- To review the role of growth factors in tumor progression.
- To examine the mechanisms by which TGF-beta and FGF families contribute to malignancy.
- To explore TGF-beta's dual role in transformation and metastasis.
Main Methods:
- Review of existing literature on growth factor involvement in cancer.
- Analysis of mechanisms of action for TGF-beta and FGF signaling in tumor progression.
- Presentation of models illustrating growth factor regulation of malignancy.
Main Results:
- TGF-beta, initially a negative regulator, promotes invasion and metastasis in advanced cancers via autocrine signaling.
- FGF family members are implicated in cancer transformation and metastasis induction.
- Specific models demonstrate TGF-beta 1's link to ribonucleotide reductase and cell proliferation.
- Autocrine/intracrine FGF signaling drives malignant cell proliferation and metastasis.
- Autocrine TGF-beta regulates cancer cell invasion and locomotion through proteolytic activity and hyaluronan/RHAMM signaling.
Conclusions:
- Growth factors, particularly TGF-beta and FGF, are critical drivers of tumor progression, invasion, and metastasis.
- Understanding these signaling pathways offers potential therapeutic targets for cancer treatment.
- TGF-beta exhibits context-dependent roles, acting as a tumor suppressor early on and a promoter of metastasis later.