Modulation of the tumor microenvironment and inhibition of EGF/EGFR pathway

Novel anti-tumor mechanisms of Cannabidiol in breast cancer

Mohamad Elbaz, Mohd W Nasser, Janani Ravi, Nissar A. Wani, Dinesh K. Ahirwar, Helong Zhao, Steve Oghumu, Abhay R. Satoskar, Konstantin Shilo, William E. Carson, Ramesh K. Ganju

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

The anti-tumor role and mechanisms of Cannabidiol (CBD), a non-psychotropic cannabinoid compound, are not well studied especially in triple-negative breast cancer (TNBC). In the present study, we analyzed CBD's anti-tumorigenic activity against highly aggressive breast cancer cell lines including TNBC subtype. We show here -for the first time-that CBD significantly inhibits epidermal growth factor (EGF)-induced proliferation and chemotaxis of breast cancer cells. Further studies revealed that CBD inhibits EGF-induced activation of EGFR, ERK, AKT and NF-kB signaling pathways as well as MMP2 and MMP9 secretion. In addition, we demonstrated that CBD inhibits tumor growth and metastasis in different mouse model systems. Analysis of molecular mechanisms revealed that CBD significantly inhibits the recruitment of tumor-associated macrophages in primary tumor stroma and secondary lung metastases. Similarly, our invitro studies showed a significant reduction in the number of migrated RAW 264.7 cells towards the conditioned medium of CBD-treated cancer cells. The conditioned medium of CBD-treated cancer cells also showed lower levels of GM-CSF and CCL3 cytokines which are important for macrophage recruitment and activation. In summary, our study shows -for the first time-that CBD inhibits breast cancer growth and metastasis through novel mechanisms by inhibiting EGF/EGFR signaling and modulating the tumor microenvironment. These results also indicate that CBD can be used as a novel therapeutic option to inhibit growth and metastasis of highly aggressive breast cancer subtypes including TNBC, which currently have limited therapeutic options and are associated with poor prognosis and low survival rates.

Original languageEnglish (US)
Pages (from-to)906-919
Number of pages14
JournalMolecular Oncology
Volume9
Issue number4
DOIs
StatePublished - Apr 1 2015

Fingerprint

Cannabidiol
Tumor Microenvironment
Epidermal Growth Factor
Breast Neoplasms
Triple Negative Breast Neoplasms
Neoplasms
Neoplasm Metastasis
Conditioned Culture Medium
Growth
Inhibition (Psychology)
Macrophage Activation
Cannabinoids
NF-kappa B
Chemotaxis
Granulocyte-Macrophage Colony-Stimulating Factor
Macrophages
Cytokines

Keywords

  • Cannabidiol
  • EGFR
  • Triple negative breast cancer
  • Tumor microenvironment

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Oncology
  • Cancer Research

Cite this

Modulation of the tumor microenvironment and inhibition of EGF/EGFR pathway : Novel anti-tumor mechanisms of Cannabidiol in breast cancer. / Elbaz, Mohamad; Nasser, Mohd W; Ravi, Janani; Wani, Nissar A.; Ahirwar, Dinesh K.; Zhao, Helong; Oghumu, Steve; Satoskar, Abhay R.; Shilo, Konstantin; Carson, William E.; Ganju, Ramesh K.

In: Molecular Oncology, Vol. 9, No. 4, 01.04.2015, p. 906-919.

Research output: Contribution to journalArticle

Elbaz, M, Nasser, MW, Ravi, J, Wani, NA, Ahirwar, DK, Zhao, H, Oghumu, S, Satoskar, AR, Shilo, K, Carson, WE & Ganju, RK 2015, 'Modulation of the tumor microenvironment and inhibition of EGF/EGFR pathway: Novel anti-tumor mechanisms of Cannabidiol in breast cancer', Molecular Oncology, vol. 9, no. 4, pp. 906-919. https://doi.org/10.1016/j.molonc.2014.12.010
Elbaz, Mohamad ; Nasser, Mohd W ; Ravi, Janani ; Wani, Nissar A. ; Ahirwar, Dinesh K. ; Zhao, Helong ; Oghumu, Steve ; Satoskar, Abhay R. ; Shilo, Konstantin ; Carson, William E. ; Ganju, Ramesh K. / Modulation of the tumor microenvironment and inhibition of EGF/EGFR pathway : Novel anti-tumor mechanisms of Cannabidiol in breast cancer. In: Molecular Oncology. 2015 ; Vol. 9, No. 4. pp. 906-919.
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