title: Modulation of the tumor microenvironment and inhibition of EGF/EGFR pathway: novel anti-tumor mechanisms of Cannabidiol in breast cancer.
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 in vitro 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.
authors: Department of Pathology, The Ohio State University, Wexner Medical Center, 43210, USA; The Comprehensive Cancer Center, The Ohio State University, Wexner Medical Center, 43210, USA. Electronic address: elbaz.2@osu.edu.
authors: Mohamad
authors: M
authors: Elbaz
authors: Department of Pathology, The Ohio State University, Wexner Medical Center, 43210, USA; The Comprehensive Cancer Center, The Ohio State University, Wexner Medical Center, 43210, USA. Electronic address: Mohd.Nasser@osumc.edu.
authors: Mohd W
authors: MW
authors: Nasser
authors: Department of Pathology, The Ohio State University, Wexner Medical Center, 43210, USA; The Comprehensive Cancer Center, The Ohio State University, Wexner Medical Center, 43210, USA. Electronic address: Janani.Ravi@osumc.edu.
authors: Janani
authors: J
authors: Ravi
authors: Department of Pathology, The Ohio State University, Wexner Medical Center, 43210, USA; The Comprehensive Cancer Center, The Ohio State University, Wexner Medical Center, 43210, USA. Electronic address: Nissar.Wani@osumc.edu.
authors: Nissar A
authors: NA
authors: Wani
authors: Department of Pathology, The Ohio State University, Wexner Medical Center, 43210, USA; The Comprehensive Cancer Center, The Ohio State University, Wexner Medical Center, 43210, USA. Electronic address: Dinesh.Ahirwar@osumc.edu.
authors: Dinesh K
authors: DK
authors: Ahirwar
authors: Department of Pathology, The Ohio State University, Wexner Medical Center, 43210, USA; The Comprehensive Cancer Center, The Ohio State University, Wexner Medical Center, 43210, USA. Electronic address: Helong.Zhao@osumc.edu.
authors: Helong
authors: H
authors: Zhao
authors: Department of Pathology, The Ohio State University, Wexner Medical Center, 43210, USA; The Comprehensive Cancer Center, The Ohio State University, Wexner Medical Center, 43210, USA. Electronic address: Steve.Oghumu@osumc.edu.
authors: Steve
authors: S
authors: Oghumu
authors: Department of Pathology, The Ohio State University, Wexner Medical Center, 43210, USA; The Comprehensive Cancer Center, The Ohio State University, Wexner Medical Center, 43210, USA. Electronic address: abhay.satoskar@osumc.edu.
authors: Abhay R
authors: AR
authors: Satoskar
authors: Department of Pathology, The Ohio State University, Wexner Medical Center, 43210, USA; The Comprehensive Cancer Center, The Ohio State University, Wexner Medical Center, 43210, USA. Electronic address: Konstantin.Shilo@osumc.edu.
authors: Konstantin
authors: K
authors: Shilo
authors: The Comprehensive Cancer Center, The Ohio State University, Wexner Medical Center, 43210, USA; Department of Surgery, The Ohio State University, Wexner Medical Center, 43210, USA. Electronic address: carson.77@osu.edu.
authors: William E
authors: WE
authors: Carson
authors: Department of Pathology, The Ohio State University, Wexner Medical Center, 43210, USA; The Comprehensive Cancer Center, The Ohio State University, Wexner Medical Center, 43210, USA. Electronic address: Ramesh.ganju@osumc.edu.
authors: Ramesh K
authors: RK
authors: Ganju
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D002185:Cannabidiol / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004815:Epidermal Growth Factor / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology / Q000556:secondary; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D009361:Neoplasm Invasiveness; D015398:Signal Transduction / Q000187:drug effects; D064726:Triple Negative Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D059016:Tumor Microenvironment / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; D002185:Cannabidiol; D004815:Epidermal Growth Factor; D066246:ErbB Receptors
keywords: Cannabidiol; EGFR; Triple negative breast cancer; Tumor microenvironment