Microparticles shed from multidrug resistant breast cancer cells provide a parallel survival pathway through immune evasion.
BACKGROUND
Breast cancer is the most frequently diagnosed cancer in women. Resident macrophages at distant sites provide a highly responsive and immunologically dynamic innate immune response against foreign infiltrates. Despite extensive characterization of the role of macrophages and other immune cells in malignant tissues, there is very little known about the mechanisms which facilitate metastatic breast cancer spread to distant sites of immunological integrity. The mechanisms by which a key healthy defense mechanism fails to protect distant sites from infiltration by metastatic cells in cancer patients remain undefined. Breast tumors, typical of many tumor types, shed membrane vesicles called microparticles (MPs), ranging in size from 0.1-1 μm in diameter. MPs serve as vectors in the intercellular transfer of functional proteins and nucleic acids and in drug sequestration. In addition, MPs are also emerging to be important players in the evasion of cancer cell immune surveillance.


METHODS
A comparative analysis of effects of MPs isolated from human breast cancer cells and non-malignant human brain endothelial cells were examined on THP-1 derived macrophages in vitro. MP-mediated effects on cell phenotype and functionality was assessed by cytokine analysis, cell chemotaxis and phagocytosis, immunolabelling, flow cytometry and confocal imaging. Student's t-test or a one-way analysis of variance (ANOVA) was used for comparison and statistical analysis.


RESULTS
In this paper we report on the discovery of a new cellular basis for immune evasion, which is mediated by breast cancer derived MPs. MPs shed from multidrug resistant (MDR) cells were shown to selectively polarize macrophage cells to a functionally incapacitated state and facilitate their engulfment by foreign cells.


CONCLUSIONS
We propose this mechanism may serve to physically disrupt the inherent immune response prior to cancer cell colonization whilst releasing mediators required for the recruitment of distant immune cells. These findings introduce a new paradigm in cancer cell biology with significant implications in understanding breast cancer colonization at distant sites. Most importantly, this is also the first demonstration that MPs serve as conduits in a parallel pathway supporting the cellular survival of MDR cancer cells through immune evasion.
Discipline of Pharmacy, The Graduate School of Health, University of Technology Sydney, PO Box 123, Broadway, Sydney, NSW, 2007, Australia.
Ritu
R
Jaiswal
iThree Institute, University of Technology Sydney, Sydney, NSW, 2007, Australia.
Michael S
MS
Johnson
Discipline of Pharmacy, The Graduate School of Health, University of Technology Sydney, PO Box 123, Broadway, Sydney, NSW, 2007, Australia.
Deep
D
Pokharel
Discipline of Pharmacy, The Graduate School of Health, University of Technology Sydney, PO Box 123, Broadway, Sydney, NSW, 2007, Australia.
S Rajeev
SR
Krishnan
Discipline of Pharmacy, The Graduate School of Health, University of Technology Sydney, PO Box 123, Broadway, Sydney, NSW, 2007, Australia. mary.bebawy@uts.edu.au.
Mary
M
Bebawy
D001943:Breast Neoplasms / Q000276:immunology* / Q000503:physiopathology; D045744:Cell Line, Tumor; D055252:Cell-Derived Microparticles / Q000502:physiology*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008264:Macrophages; D019139:Tumor Escape
Cancer; Cell engulfment; Extracellular vesicles; Immune evasion; Macrophage; Microparticles; Multidrug resistance