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

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.

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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

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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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Correspondence to José Vázquez-Prado.

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Cervantes-Villagrana, R.D., Color-Aparicio, V.M., Reyes-Cruz, G. et al. Protumoral bone marrow-derived cells migrate via Gβγ-dependent signaling pathways and exhibit a complex repertoire of RhoGEFs. J. Cell Commun. Signal. 13, 179–191 (2019). https://doi.org/10.1007/s12079-018-00502-6

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Keywords

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