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Studying the Effects of Tumor-Secreted Paracrine Ligands on Macrophage Activation using Co-Culture with Permeable Membrane Supports
Published on: November 28, 2019
Non-cell autonomous or secretory tumor suppression
Christelle En Lin Chua1, Shu Ning Chan, Bor Luen Tang
1Department of Biochemistry, Yong Loo Lin School of Medicine National University Health System, Singapore, Singapore; NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore, Singapore.
Abstract:
Many malignancies result from deletions or loss-of-function mutations in one or more tumor suppressor genes, the products of which curb unrestrained growth or induce cell death in those with dysregulated proliferative capacities. Most tumor suppressors act in a cell autonomous manner, and only very few proteins are shown to exert a non-cell autonomous tumor suppressor function on other cells. Examples of these include members of the secreted frizzled-related protein (SFRP) family and the secreted protein acidic and rich in cysteine (SPARC)-related proteins. Very recent findings have, however, considerably expanded our appreciation of non-cell autonomous tumor suppressor functions. Broadly, this may occur in two ways. Intracellular tumor suppressor proteins within cells could in principle inhibit aberrant growth of neighboring cells by conditioning an antitumor microenvironment through secreted factors. This is demonstrated by an apparent non-cell autonomous tumor suppressing property of p53. On the other hand, a tumor suppressor produced by a cell may be secreted extracellularly, and taken up by another cell with its activity intact. Intriguingly, this has been recently shown to occur for the phosphatase and tensin homolog (PTEN) by both conventional and unconventional modes of secretion. These recent findings would aid the development of therapeutic strategies that seek to reinstate tumor suppression activity in therapeutically recalcitrant tumor cells, which have lost it in the first place.
Insights
Tumor suppressor genes normally prevent cancer. Recent discoveries reveal some tumor suppressors can act outside their own cells, influencing neighboring cells to inhibit tumor growth.
Area of Science:
- Cancer Biology
- Molecular Oncology
- Cellular Signaling
Background:
- Malignancies often arise from loss-of-function mutations in tumor suppressor genes.
- Most tumor suppressors function within the cell where they are produced (cell-autonomous).
- A limited number of proteins exhibit non-cell autonomous tumor suppressor activity.
Purpose of the Study:
- To explore the expanding understanding of non-cell autonomous tumor suppressor functions.
- To highlight mechanisms by which tumor suppressors can impact neighboring cells.
- To discuss implications for developing novel cancer therapies.
Main Methods:
- Review of recent scientific literature on non-cell autonomous tumor suppressor mechanisms.
- Analysis of examples including secreted frizzled-related proteins (SFRPs), SPARC-related proteins, p53, and phosphatase and tensin homolog (PTEN).
- Discussion of intracellular and extracellular secretion pathways for tumor suppressor action.
Main Results:
- Non-cell autonomous tumor suppression can occur via secreted factors conditioning an anti-tumor microenvironment (e.g., p53).
- Tumor suppressors can be secreted and taken up by other cells, retaining activity (e.g., PTEN).
- Both conventional and unconventional secretion pathways contribute to non-cell autonomous PTEN function.
Conclusions:
- The concept of non-cell autonomous tumor suppression is broader than previously appreciated.
- Understanding these mechanisms offers new therapeutic avenues for recalcitrant tumors.
- Targeting extracellular tumor suppressor activity could overcome resistance in cancer treatment.
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