title: Invasive breast carcinoma cells from patients exhibit MenaINV- and macrophage-dependent transendothelial migration.
abstract: Metastasis is a complex, multistep process of cancer progression that has few treatment options. A critical event is the invasion of cancer cells into blood vessels (intravasation), through which cancer cells disseminate to distant organs. Breast cancer cells with increased abundance of Mena [an epidermal growth factor (EGF)-responsive cell migration protein] are present with macrophages at sites of intravasation, called TMEM sites (for tumor microenvironment of metastasis), in patient tumor samples. Furthermore, the density of these intravasation sites correlates with metastatic risk in patients. We found that intravasation of breast cancer cells may be prevented by blocking the signaling between cancer cells and macrophages. We obtained invasive breast ductal carcinoma cells of various subtypes by fine-needle aspiration (FNA) biopsies from patients and found that, in an in vitro transendothelial migration assay, cells that migrated through a layer of human endothelial cells were enriched for the transcript encoding Mena(INV), an invasive isoform of Mena. This enhanced transendothelial migration required macrophages and occurred with all of the breast cancer subtypes. Using mouse macrophages and the human cancer cells from the FNAs, we identified paracrine and autocrine activation of colony-stimulating factor-1 receptor (CSF-1R). The paracrine or autocrine nature of the signal depended on the breast cancer cell subtype. Knocking down Mena(INV) or adding an antibody that blocks CSF-1R function prevented transendothelial migration. Our findings indicate that Mena(INV) and TMEM frequency are correlated prognostic markers and CSF-1 and Mena(INV) may be therapeutic targets to prevent metastasis of multiple breast cancer subtypes.
authors.affiliation: Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA. moktay@montefiore.org jeanine.pignatelli@einstein.yu.edu john.condeelis@einstein.yu.edu.
authors.forename: Jeanine
authors.initials: J
authors.lastname: Pignatelli
authors.affiliation: Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA. Department of Biology, Yeshiva University, New York, NY 10033, USA.
authors.forename: Sumanta
authors.initials: S
authors.lastname: Goswami
authors.affiliation: Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA. Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY 10461, USA. Department of Pathology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY 10467, USA. Integrated Imaging Program, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Joan G
authors.initials: JG
authors.lastname: Jones
authors.affiliation: Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Rohan
authors.affiliation: Department of Biology, Yeshiva University, New York, NY 10033, USA.
authors.forename: Evan
authors.initials: E
authors.lastname: Pieri
authors.affiliation: Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY 10467, USA.
authors.forename: Esther
authors.initials: E
authors.lastname: Adler
authors.affiliation: Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Dianne
authors.initials: D
authors.lastname: Cox
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY 10467, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Maleki
authors.affiliation: Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Anne
authors.initials: A
authors.lastname: Bresnick
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Frank B
authors.initials: FB
authors.lastname: Gertler
authors.affiliation: Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA. Integrated Imaging Program, Albert Einstein College of Medicine, Bronx, NY 10461, USA. Gruss Lipper Biophotonics Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA. moktay@montefiore.org jeanine.pignatelli@einstein.yu.edu john.condeelis@einstein.yu.edu.
authors.forename: John S
authors.initials: JS
authors.lastname: Condeelis
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY 10467, USA. moktay@montefiore.org jeanine.pignatelli@einstein.yu.edu john.condeelis@einstein.yu.edu.
authors.forename: Maja H
authors.initials: MH
authors.lastname: Oktay
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D019898:Autocrine Communication; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics; D044963:Biopsy, Fine-Needle; D001943:Breast Neoplasms / Q000737:chemistry / Q000235:genetics / Q000473:pathology*; D015820:Cadherins / Q000096:biosynthesis / Q000235:genetics; D018270:Carcinoma, Ductal, Breast / Q000737:chemistry / Q000145:classification / Q000235:genetics / Q000473:pathology*; D018920:Coculture Techniques; D042783:Endothelial Cells / Q000166:cytology; D005091:Exons; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008264:Macrophages / Q000502:physiology*; D051379:Mice; D008840:Microfilament Proteins / Q000032:analysis* / Q000235:genetics / Q000502:physiology; D058990:Molecular Targeted Therapy; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness / Q000503:physiopathology*; D009363:Neoplasm Proteins / Q000032:analysis* / Q000235:genetics / Q000502:physiology; D019899:Paracrine Communication; D011379:Prognosis; D020033:Protein Isoforms / Q000032:analysis / Q000235:genetics / Q000502:physiology; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000502:physiology; D015398:Signal Transduction; D057705:Transendothelial and Transepithelial Migration / Q000502:physiology*; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment
chemical_list: D014408:Biomarkers, Tumor; D015820:Cadherins; C511939:Enah protein, human; D008840:Microfilament Proteins; D009363:Neoplasm Proteins; D020033:Protein Isoforms; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D016186:Receptor, Macrophage Colony-Stimulating Factor