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The idea that a tumour, whether primary or metastatic, needs to establish a blood supply in order to expand is now taken as read. However, what enables this process is still under investigation. A recent paper by Vivek Mittal and colleagues adds weight to the argument that bone marrow (BM)-derived endothelial progenitor cells (EPCs) are important players, this time in the establishment of macrometastases.

Mittal and colleagues transplanted two labelled populations of cells into syngeneic mice — BM cells expressing green fluorescent protein (GFP) and, once the new BM was established, Lewis lung carcinoma cells expressing red fluorescent protein. The resultant pulmonary macrometastases developed a blood supply in which 12.7 2.9% of total endothelial cells were clearly BM-derived (GFP⁺, CD31⁺ and able to bind a circulating exogenous endothelial specific isolectin, Griffonia simplicifolia IB4 (GSIB4)). A spontaneous mouse model of breast cancer that metastasizes to the lungs was used to verify these findings, with 11.7% 3.7% of endothelial cells being BM-derived and GFP⁺. Both models indicated that the lungs of mice with micrometastases had significantly increased numbers of GFP⁺ BM-derived EPCs, and further analyses implied that the expression of vascular cell adhesion molecule 1 by the new blood vessels might be involved in recruiting BM-derived EPCs, which express the cognate receptor integrin 41.

To ascertain whether BM-derived EPCs are needed for the progression from micrometastases to macrometastases, the authors investigated the expression of Id1, which is important for tumour angiogenesis involving BM-derived cells. The authors showed that BM-derived EPCs express Id1 in tumour-bearing mice and Id1 expression is confined to EPCs. By using a doxycycline-regulatable short hairpin RNA to knockdown Id1 in BM cells during metastasis progression, the authors showed that loss of Id1 significantly impaired the growth of macrometastases, but had no effect on the numbers of micrometastases. Importantly, the numbers of circulating BM-derived EPCs were reduced by Id1 knockdown, whereas the levels of other BM-derived cells were unchanged.

The authors conclude that anti-angiogenic therapies might be of use in preventing the growth of lung metastases, but note that the course of metastatic disease progression differs between mouse and man.

Author: Nicola McCarthy