ARTICLE 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. Cancer Res; 73(14); 4233–46. ©2013 AACR.
