Unravelling the molecular mechanisms behind tumourigenic effects
The TGF-ß cytokine is a prototype in a large family of growth regulatory factors, and it plays a number of important roles during tumour progression. Researchers are investigating the molecular mechanisms behind how TGF-ß activates its pro-tumourigenic signalling pathways, which could help uncover new targets for drug development, as Professor Carl-Henrik Heldin explains.
The Transforming Growth Factor-ß (TGF-ß) cytokine performs a variety of different roles in tumour progression. It makes tumour cells more invasive and prone to forming metastasis, while it also has other pro-tumourigenic effects. “For example. it inhibits the immune system, and promotes angiogenesis, as well as the development of cancer-associated fibroblasts,” outlines Carl-Henrik Heldin, Professor in Molecular Cell Biology at Uppsala University. As the head of an ERC-backed project based at the University, Professor Heldin is investigating the underlying mechanisms behind these pro-tumourigenic effects, which contrast sharply with its role before a tumour is established. “Initially TGF-ß is actually a tumour-suppressor, as it inhibits the growth of most normal cells and induces apoptosis of many cell types. These
Mechanism by which TGFb activates Src
cancer is a fairly benign disease, and it only really threatens us when it starts to invade the surrounding environment and spread through the body.”
Initially TGF-ß is a tumour-suppressor, as it inhibits the growth of most normal cells and induces apoptosis of many cell types. As a tumour progresses there is a kind of switch, which converts TGF-ß from being a tumour-suppressor to a tumour promoter.
are tumour-suppressive effects,” he explains. “As a tumour progresses there is a kind of switch, which converts TGF-ß from being a tumour-suppressor to a tumour promoter.”
TGF-ß inhibitors
This means a great deal of care needs to be taken in treating tumour patients with TGF-ß inhibitors and avoiding unintended side-effects. The wider aim for Professor Heldin and his colleagues is to help find ways of selectively inhibiting the protumourigenic signalling pathways in tumour cells, while leaving the tumour-suppressive pathways unperturbed. “We are trying to figure out the molecular mechanisms behind why TGF-ß activates various signalling pathways,” he says. The vast majority of cancer-related deaths are caused by the cancer spreading, so an effective method of inhibiting or slowing down that spread could have a significant impact. “A large group of patients could benefit,” stresses Professor Heldin. “For example, in most cases prostate
There are TGF-ß receptors on essentially all cell types, reinforcing the wider relevance of this research. Perturbation of TGF-ß signalling is also involved in several other diseases, including certain inflammatory conditions and fibrotic disorders, as Professor Heldin explains. “TGF-ß is a very powerful stimulator of matrix proteins for instance, a process that is involved in fibrosis. This has stimulated a lot of interest, and TGF-ß inhibitors have been discussed as possible therapeutic agents in fibrosis,” he says. This work holds wider relevance to the pharmaceutical industry, and Professor Heldin’s research represents an important contribution to the goal of developing more effective treatments. “We eventually hope to provide targets for drug discovery,” he continues. “However, the whole process of drug development cannot really take place in an academic setting – we need further input and collaboration.”
Progress has been made over the course of the project in terms of selectively inhibiting
the pro-tumourigenic pathways, and Professor Heldin hopes to build on this further, with plans in the pipeline for continued investigation. “We are pursuing several lines of research into how TGF-ß activates various signalling pathways, and we hope to make more progress in future,” he says.
SelectiveTGFb-inhib
Pro-tumorigenic effects of TGFbelucidation of mechanisms and development of selective inhibitors
Carl-Henrik Heldin
Professor in Molecular Cell Biology
Dept. of Medical Biochemistry and Microbiology
Box 582, Biomedical Center
Uppsala University SE-751 23 Uppsala, Sweden
T: +46-18-4714738
E: C-H.Heldin@imbim.uu.se
W: https://www.katalog.uu.se/ profile/?id=N96-1274
Carl-Henrik Heldin is a Professor in the Department of Medical Biochemistry and Microbiology at Uppsala University. His main research interest is the mechanisms of signal transduction by growth regulatory factors, as well as their normal function and role in disease.
