title: Bone marrow-derived CD11b+Jagged2+ cells promote epithelial-to-mesenchymal transition and metastasization in colorectal cancer.
abstract: Timely detection of colorectal cancer metastases may permit improvements in their clinical management. Here, we investigated a putative role for bone marrow-derived cells in the induction of epithelial-to-mesenchymal transition (EMT) as a marker for onset of metastasis. In ectopic and orthotopic mouse models of colorectal cancer, bone marrow-derived CD11b(Itgam)(+)Jagged2 (Jag2)(+) cells infiltrated primary tumors and surrounded tumor cells that exhibited diminished expression of E-cadherin and increased expression of vimentin, 2 hallmarks of EMT. In vitro coculture experiments showed that the bone marrow-derived CD11b(+)Jag2(+) cells induced EMT through a Notch-dependent pathway. Using neutralizing antibodies, we imposed a blockade on CD11b(+) cells' recruitment to tumors, which decreased the tumor-infiltrating CD11b(+)Jag2(+) cell population of interest, decreasing tumor growth, restoring E-cadherin expression, and delaying EMT. In support of these results, we found that peripheral blood levels of CD11b(+)Jag2(+) cells in mouse models of colorectal cancer and in a cohort of untreated patients with colorectal cancer were indicative of metastatic disease. In patients with colorectal cancer, the presence of circulating CD11b(+)Jag2(+) cells was accompanied by loss of E-cadherin in the corresponding patient tumors. Taken together, our results show that bone marrow-derived CD11b(+)Jag2(+) cells, which infiltrate primary colorectal tumors, are sufficient to induce EMT in tumor cells, thereby triggering onset of metastasis. Furthermore, they argue that quantifying circulating CD11b(+)Jag2(+) cells in patients may offer an indicator of colorectal cancer progression to metastatic levels of the disease.
authors.affiliation: Angiogenesis Lab, CIPM, Department of Gastroenterology, and Histopathology Unit, Portuguese Institute of Oncology, IPOLFG, EPE, Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, Lisbon, and Instituto Gulbenkian de Ciência, Oeiras, Portugal.
authors.forename: Francisco
authors.initials: F
authors.lastname: Caiado
authors.forename: Tânia
authors.initials: T
authors.lastname: Carvalho
authors.forename: Isadora
authors.initials: I
authors.lastname: Rosa
authors.forename: Leonor
authors.initials: L
authors.lastname: Remédio
authors.forename: Ana
authors.initials: A
authors.lastname: Costa
authors.forename: João
authors.initials: J
authors.lastname: Matos
authors.forename: Beate
authors.initials: B
authors.lastname: Heissig
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Koichi
authors.initials: K
authors.lastname: Hattori
authors.forename: João Pereira
authors.initials: JP
authors.lastname: da Silva
authors.forename: Paulo
authors.initials: P
authors.lastname: Fidalgo
authors.forename: António Dias
authors.initials: AD
authors.lastname: Pereira
authors.forename: Sérgio
authors.initials: S
authors.lastname: Dias
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology*; D039481:CD11b Antigen / Q000235:genetics / Q000378:metabolism*; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D014746:Vimentin / Q000235:genetics / Q000378:metabolism
chemical_list: D039481:CD11b Antigen; D015820:Cadherins; D036341:Intercellular Signaling Peptides and Proteins; D051880:Receptors, Notch; D014746:Vimentin