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TNF-α Modulates P-Glycoprotein Expression and Contributes to Cellular Proliferation via Extracellular Vesicles

Tandressa Berguetti1,2, Lucas S P Quintaes3, Thais Hancio4,5

  • 1Laboratório de Hemato-Oncologia Celular e Molecular, Programa de Hemato-Oncologia Molecular, Instituto Nacional de Câncer (INCA), Rio de Janeiro 20231-050, Brazil. tata.berguetti@hotmail.com.

Cells
|May 30, 2019
PubMed

Insights

Cancer cells utilize P-glycoprotein (Pgp) and Tumor Necrosis Factor-alpha (TNF-α) within extracellular vesicles to promote malignancy. These vesicles influence non-tumor cell proliferation, suggesting a role in cancer progression.

Area of Science:

  • Cancer Biology
  • Cellular Malignancy
  • Extracellular Vesicles

Background:

  • P-glycoprotein (Pgp/ABCB1) overexpression is a key driver of multidrug resistance (MDR) in cancer chemotherapy.
  • Tumor Necrosis Factor-alpha (TNF-α), a cytokine, can influence both cell death and tumor growth, potentially impacting MDR.
  • Extracellular vesicles (EVs), including membrane microparticles (MP), are implicated in intercellular communication and disease progression.

Purpose of the Study:

  • To investigate the role of Pgp and TNF-α transported by extracellular vesicles in cancer cell self-maintenance and malignancy.
  • To explore the interplay between endogenous and recombinant TNF-α (rTNF-α) and Pgp expression and function in MDR cancer models.
  • To determine the effect of MP released by cancer cells on recipient cells.

Main Methods:

  • Utilized a classical in vitro multidrug-resistant (MDR) cancer model.
  • Analyzed the correlation between endogenous TNF-α and Pgp expression.
  • Assessed the impact of recombinant TNF-α (rTNF-α) incubation on Pgp expression and efflux function.
  • Characterized MP released from parental and MDR cells for TNF-α and Pgp content.
  • Evaluated the effect of released MP on non-cancer recipient cells and non-tumor cell proliferation.

Main Results:

  • A positive correlation was observed between endogenous TNF-α and Pgp in MDR cells, potentially modulating rTNF-α's cytotoxic effects.
  • rTNF-α incubation led to reduced Pgp expression and efflux function, alongside a positive feedback loop in TNF-α regulation.
  • Parental and MDR cells released MP containing endogenous TNF-α and Pgp, but these were not transferred to non-cancer cells.
  • MP released from cancer cells increased the proliferation index of non-tumor cells.

Conclusions:

  • Pgp and endogenous TNF-α positively regulate cancer cell malignancy.
  • Cancer-derived MP can alter the behavior of normal cells, suggesting a role in tumor microenvironment modulation.
  • These findings highlight a novel mechanism by which cancer cells promote their own survival and influence surrounding cells.
Keywords:
ABCB1MDRP-glycoproteinTNF-αdrug resistanceextracellular vesiclesmicroparticles

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