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Protumoral bone marrow-derived cells migrate via Gβγ-dependent signaling pathways and exhibit a complex repertoire of RhoGEFs

  • Rodolfo Daniel Cervantes-Villagrana
  • Víctor Manuel Color-Aparicio
  • Guadalupe Reyes-Cruz
  • José Vázquez-PradoEmail author
Article

Abstract

Reciprocal communication among cells of the tumor microenvironment contributes to cancer progression. Here, we show that a protumoral population of cultured bone marrow-derived cells (BMDC) containing Tie2+/CD45+/CD11b + cells responded to lung carcinoma cells and reciprocally stimulated them. These cells migrated via heterotrimeric G protein-dependent signaling pathways and strongly activated the PI3K/AKT, ERK and mTOR signaling cascades in response to conditioned media and chemotactic agonists. To get insight into the molecular machinery involved in BMDC migration, we revealed their repertoire of guanine nucleotide exchange factors for Rho GTPases (RhoGEFs) and G proteins in comparison with fresh bone marrow cells, proven that these cell populations had contrasting effects on tumor growth. BMDC exhibited a higher expression of G protein regulated RhoGEFs including P-Rex1, PDZ-RhoGEF, LARG, Trio and some less well characterized RhoGEFs such as ARHGEF5, ARHGEF17 and PLEKHG6. G proteins such as Gα12/13, Gαq, and the small GTPase RhoJ were also highly expressed in BMDC. Our results indicate that Tie2+/CD45+/CD11b + BMDC express a unique variety of chemotactic transducers and effectors potentially linked to their protumoral effect, warranting further studies to their characterization as molecular targets.

Keywords

Cell migration GPCRs Protumoral bone marrow-derived cells RhoGEFs Rho GTPases Tie2-monocyte/macrophages 

Abbreviations

VEGF

Vascular Endothelial Growth Factor

SDF-1

Stromal Cell-Derived Factor 1

S1P1R

Sphingosine-1-Phosphate Receptors

S1P

Sphingosine-1-phosphate

IL-8

Interleukin-8

RhoGEFs

Rho guanine exchange factors

P-Rex1

Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 1 protein

PH

Pleckstrin homology domain

PAE

Porcine Aortic Endothelial

mTOR

mammalian target of rapamycin

LPA

Lysophosphatidic acid

LLC

Lewis lung carcinoma

HGF

Hepatocyte Growth Factor

EPC

Endothelial Progenitor Cell

EGF

Epidermal Growth Factor

FGF

Fibroblast Growth Factor

DH

Dbl-Homology domain

BMDC

Bone Marrow-Derived Cells

BM

Bone Marrow

Notes

Acknowledgments

Technical assistance provided by Estanislao Escobar-Islas, Margarita Valadez, David Pérez, and Jaime Estrada-Trejo is acknowledged. We thank Victor Hugo Rosales-García (Central Laboratories of Cinvestav) for technical assistance in cytometry; and Ricardo Gaxiola-Centeno and Benjamín Emmanuel Chavez-Álvarez (UPEAL-Cinvestav) for breeding and maintaining mice colonies. This work was supported by CONACyT (Consejo Nacional de Ciencia y Tecnología, Mexico) Grants 286274 (to J. V.-P.) and 240119 (to G. R.-C.). R.D.C.-V., and V.M.C.-A were supported by fellowships from CONACyT.

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Copyright information

© The International CCN Society 2019

Authors and Affiliations

  • Rodolfo Daniel Cervantes-Villagrana
    • 1
  • Víctor Manuel Color-Aparicio
    • 1
  • Guadalupe Reyes-Cruz
    • 2
  • José Vázquez-Prado
    • 1
    Email author
  1. 1.Department of PharmacologyCINVESTAV-IPNMexico CityMexico
  2. 2.Department of Cell BiologyCINVESTAV-IPNMexico CityMexico

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