Exploiting agonist biased signaling of chemokines to target cancer
Ishan Roy1, Anthony E Getschman2, Brian F Volkman2
1Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin.
Abstract:
As knowledge of growth-independent functions of cancer cells is expanding, exploration into the role of chemokines in modulating cancer pathogenesis, particularly metastasis, continues to develop. However, more study into the mechanisms whereby chemokines direct the migration of cancer cells is needed before specific therapies can be generated to target metastasis. Herein, we draw attention to the longstanding conundrum in the field of chemokine biology that chemokines stimulate migration in a biphasic manner; and explore this phenomenon's impact on chemokine function in the context of cancer. Typically, low concentrations of chemokines lead to chemotactic migration and higher concentrations halt migration. The signaling mechanisms that govern this phenomenon remain unclear. Over the last decade, we have defined a novel signaling mechanism for regulation of chemokine migration through ligand oligomerization and biased agonist signaling. We provide insight into this new paradigm for chemokine signaling and discuss how it will impact future exploration into chemokine function and biology. In the pursuit of producing more novel cancer therapies, we suggest a framework for pharmaceutical application of the principles of chemokine oligomerization and biased agonist signaling in cancer. © 2016 Wiley Periodicals, Inc.
Insights
Chemokines guide cancer cell migration in a biphasic manner, with low concentrations promoting movement and high concentrations inhibiting it. Understanding this chemokine signaling mechanism is key for developing new anti-metastasis cancer therapies.
Area of Science:
- Oncology
- Immunology
- Cell Biology
Background:
- Cancer cell metastasis is a major challenge in oncology.
- Chemokines play a critical role in cancer pathogenesis and metastasis.
- The precise mechanisms by which chemokines regulate cancer cell migration are not fully understood.
Purpose of the Study:
- To investigate the biphasic migration response of cancer cells to chemokines.
- To elucidate the novel signaling mechanisms underlying chemokine-directed cancer cell migration.
- To explore the therapeutic potential of targeting chemokine signaling in cancer metastasis.
Main Methods:
- Analysis of chemokine-induced cancer cell migration at varying concentrations.
- Investigation of ligand oligomerization and biased agonist signaling pathways.
- Development of a framework for pharmaceutical applications.
Main Results:
- Chemokines exhibit a biphasic effect on cancer cell migration: chemotaxis at low concentrations and inhibition at high concentrations.
- Ligand oligomerization and biased agonist signaling represent a novel mechanism regulating this phenomenon.
- This signaling paradigm offers new insights into chemokine function in cancer.
Conclusions:
- The biphasic nature of chemokine signaling is crucial for understanding cancer metastasis.
- Targeting chemokine oligomerization and biased signaling presents a promising strategy for novel cancer therapies.
- Further research into these mechanisms can lead to effective anti-metastasis treatments.
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