The evidence for and against different modes of tumour cell extravasation in the lung: diapedesis, capillary destruction, necroptosis, and endothelialization

Abstract

The development of lung metastasis is a significant negative prognostic factor for cancer patients. The extravasation phase of lung metastasis involves interactions of tumour cells with the pulmonary endothelium. These interactions may have broad biological and medical significance, with potential clinical implications ranging from the discovery of lung metastasis biomarkers to the identification of targets for intervention in preventing lung metastases. Because of the potential significance, the mechanisms of tumour cell extravasation require cautious, systematic studies. Here, we discuss the literature pertaining to the proposed mechanisms of extravasation and critically compare a recently proposed mechanism (tumour cell-induced endothelial necroptosis) with the already described extravasation mechanisms in the lung. We also provide novel data that may help to explain the underlying physiological basis for endothelialization as a mechanism of tumour cell extravasation in the lung.

Hostile takeover: how tumours hijack pre‐existing vascular environments to thrive

“…In contrast, transforming growth factor‐β1 and periostin were identified as factors released from activated endothelial cells that sparked dormant micrometastatic outgrowth , which is in line with the findings of other groups, who showed that endothelial cell activation was able to drive dormant cells into a proliferative state . The recently observed localization of extravasating/extravasated cancer cells between endothelial cells and the vascular BM, termed ‘endothelialization’, might explain why cancer cells maintain endothelial and BM factors under such strict control during dormancy and its loss .…”

Response of the neurovascular unit to brain metastatic breast cancer cells

“…Endothelial protrusions covering extravasating cells were seen in vivo as well [10], and this seems to be the mechanism of the formation of multiple channels within a vessel. This type of transmigration has been previously described as “endothelial covering-type extravasation” in a zebrafish model of HeLa tumour formation [14] and “endothelization” in a mouse pulmonary melanoma metastasis model [18, 26].…”

“…Another interesting observation of our study is that tumour cells breach the glia limitans perivascularis during their extravasation. This is important because immune cells – diapedesis of which is used as a reference in deciphering mechanisms of extravasation of tumour cells [26, 31] – also have to migrate through the glia limitans perivascularis to induce neuro-inflammation [6, 11]. However, as a metastatic lesion is growing, AQP4-positive astrocyte end-feet are disappearing from the vessel to cover the surface of the tumour, from which reactive astrocytes are completely expelled.…”

Necroptotic cell death in anti‐cancer therapy

“…The authors showed that p38/HSP27 activation of RIPK3‐null endothelial cells is decreased in response to permeability factors, such as vascular endothelial growth factor, due to decreased vessel permeability. Since other mechanisms of extravasation have been proposed, more studies are needed to understand how necroptosis and RIPK3 are involved in this complex process of metastasis. Understanding this is important for treatment of metastases and development of clinically relevant anti‐metastatic therapies.…”