Abstract
The biochemical and biological mechanisms metastatic cancer cells use to function as communities and thwart internal and external growth control mechanisms remain undefined. In this work, we present the hypothesis that cancer cells may use a Quorum-Sensing mechanism to regulate multicellular functions and control steps in metastatic colonization. Quorum sensing is a bacterial cell-cell communication process used to track increasing cell-population density and, in response to changes in cell number, coordinate gene expression and behavior on a community-wide scale. Important parallels between the behavior of societies of bacterial cells and societies of malignant cancer cells exist in the bacterial literature. Of relevance to metastasis is the finding that pathogenic bacteria use quorum sensing to determine when their population numbers are high enough to collectively form biofilms in or on host organisms. Biofilms are complex, heterogeneous communities of bacterial cells encased within an extracellular matrix attached to a solid surface. Biofilms exacerbate disease and are refractory to a battery of therapies. We suggest that the quorum-sensing-controlled bacterial biofilm formation process closely parallels the steps in metastatic colonization. Cells migrate toward/on target surfaces (organ-specific homing), show cell-cell and cell-matrix interactions (tumor cell-stromal cell crosstalk), remain subclinical until they can mount an effective attack (dormancy), form complex structures with channels for nutrient flow (vascularized lesions), and contain resistant cells which can cause disease recurrence (persistors). Using ovarian cancer as an example, we present data supporting the connection between metastatic colonization and quorum sensing and discuss the implications for understanding and controlling metastasis formation.
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Abbreviations
- d:
-
Density of cells injected
- dpi:
-
Days post injection
- EPS:
-
Extracellular polysaccharide substance
- HA:
-
Hemagglutinin
- JNK:
-
c-Jun NH2 terminal protein kinase
- MAPK:
-
Mitogen-activate protein kinase
- MKK4/SEK1:
-
Mitogen-activated protein kinase kinase 4/stress-activated protein/Erk kinase 1
- MKK4-KR:
-
Mitogen-activated protein kinase kinase 4-kinase inactive
- N:
-
Number of cells injected
- PCR:
-
Polymerase chain reaction
- SAPK:
-
Stress-activated protein kinase
- SCID:
-
Severe combined immunodeficient
- t:
-
Length of experiment
- Y:
-
Yield of experimental metastases
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Acknowledgments
We thank Mr. Edwin F. Schaeffer III for his insightful discussions and comments which prompted us to first explore the potential link between our data and the quorum-sensing literature. We also thank Dr. Charles B. Brendler for his strong, unwavering, and enthusiastic intellectual, financial, and academic support. We appreciate the encouragement and thoughtful discussions from Dr. Mitchell Sokoloff and for Dr. John Isaacs’ penetrating insights into MKK4-mediated suppression of proliferation. We also thank Dr. Michael Lotze for his encouragement to publish our quorum sensing concepts. We wish to specifically recognize critical, early support from The Department of Defense, The Arthur (MacNeal) Foundation, The Lehman Brothers Foundation, and The University of Chicago Department of Surgery Huggins Competition. This work was specifically funded by The University of Chicago RESCUE Fund (CWR-S); DOD Ovarian Cancer Research Grant DAMD17-03-1-0169 (JH, DY), Grant RO1 CA 89569 (CWR-S, JH), DOD Ovarian Cancer Research Grant W81XWH-06-1-0041 (CWR-S), Arthur Foundation (J.O, CWR-S), Lehman Brothers Foundation (CWR-S), and Gynecologic Cancer Foundation/Ann Schreiber Ovarian Cancer Research Grant (JH).
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Hickson, J., Diane Yamada, S., Berger, J. et al. Societal interactions in ovarian cancer metastasis: a quorum-sensing hypothesis. Clin Exp Metastasis 26, 67–76 (2009). https://doi.org/10.1007/s10585-008-9177-z
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DOI: https://doi.org/10.1007/s10585-008-9177-z