Active versus passive mechanisms in metastasis: do cancer cells crawl into vessels, or are they pushed?

Abstract

Although millions of cells are shed from a tumour every day, haematogenous metastasis is believed to be very inefficient. This inefficiency is widely assumed to be a result of the destruction of cells in the bloodstream by shear stress and the immune system and a slow rate of extravasation and proliferation in the stroma at a secondary site. Here, we propose that, whereas active intravasation of cells into the circulation is important in some tumours, others might shed cells passively into the blood or lymphatic vessels without the involvement of active cell migration. We discuss the evidence for and against this passive-shedding hypothesis and the implications for future treatments.

Figure 1. Active and passive mechanisms in initial steps of metastasis

Left: reports that cancer cells accumulate mutations, upregulate migration machinery, and align and migrate up nutrient or chemokine gradients, are in support of active metastasis. Fibroblasts, macrophages, or other stromal cells are also likely to cooperate with cancer cells to actively help with the initial stage of metastasis. Right: however, there is evidence that many dead cells are shed into the vasculature, which implies a passive mechanism. It is possible that uncontrolled focal growth crushes or impinges upon fragile tumour blood vessels, leading to passive shedding. Similarly, fluid oozing from the tumour surface might help with shedding of cancer cells into lymphatic vessels.