Initial steps of metastasis: Cell invasion and endothelial transmigration

Abstract

Metastasis is the leading cause of cancer mortality. The metastatic cascade represents a multi-step process which includes local tumor cell invasion, entry into the vasculature followed by the exit of carcinoma cells from the circulation and colonization at the distal sites. At the earliest stage of successful cancer cell dissemination, the primary cancer adapts the secondary site of tumor colonization involving the tumor–stroma crosstalk. The migration and plasticity of cancer cells as well as the surrounding environment such as stromal and endothelial cells are mandatory. Consequently, the mechanisms of cell movement are of utmost relevance for targeted intervention of which three different types have been reported. Tumor cells can migrate either collectively, in a mesenchymal or in an amoeboid type of movement and intravasate the blood or lymph vasculature. Intravasation by the interaction of tumor cells with the vascular endothelium is mechanistically poorly understood. Changes in the epithelial plasticity enable carcinoma cells to switch between these types of motility. The types of migration may change depending on the intervention thereby increasing the velocity and aggressiveness of invading cancer cells. Interference with collective or mesenchymal cell invasion by targeting integrin expression or metalloproteinase activity, respectively, resulted in an amoeboid cell phenotype as the ultimate exit strategy of cancer cells. There are little mechanistic details reported in vivo showing that the amoeboid behavior can be either reversed or efficiently inhibited. Future concepts of metastasis intervention must simultaneously address the collective, mesenchymal and amoeboid mechanisms of cell invasion in order to advance in anti-metastatic strategies as these different types of movement can coexist and cooperate. Beyond the targeting of cell movements, the adhesion of cancer cells to the stroma in heterotypic circulating tumor cell emboli is of paramount relevance for anti-metastatic therapy.

Effects of Scrophularia extracts on tumor cell proliferation, death and intravasation through lymphoendothelial cell barriers

“…Treating LEC monolayers with 1 µM synthetic 12(S)-HETE, a metabolite of arachidonic acid generated by ALOX12/15, caused the phosphorylation of MLC2 (16) indicating that 12(S)-HETE induced the motility of LECs thereby provoking an early step of metastasis (15,17). This observation is also consistent with an inflammatory process, which is accompanied by the acquisition of a mobile phenotype of the affected cells reflecting 'epithelial to mesenchymal transition' [EMT; (57)]. Interestingly, the extract of S. lucida activated the mobility marker MLC2 (data not shown).…”

“…According to the critical role of MMPs in tumour invasion, metastasis and neovascularisation, the inhibition of the degradation of components of the extracellular matrix is a promising approach for the prevention of cancer progression. In order to develop distal metastasis a tumour cell has to encompass different steps: local infiltration into the adjacent tissue, intravasation, survival within the circulatory system, extravasation and subsequent proliferation leading to colonization (57,59). Inhibiting the first steps of this multi-step process should be a major goal of cancer therapy.…”

Regulation of Cancer Cell Behavior by the Small GTPase Rab13

“…Loss of cell-cell adhesion is an important component of cell transformation in cancer, as cells must dissociate from each other to become more migratory. This is particularly important for single cell metastasis, but also in collective cell migration where cells must detach from the original tissue, and single cells may also detach from the collectively moving cell mass (61). Furthermore, weakening of tight junctions in vascular endothelial cells allows malignant cells to escape the vasculature as part of the metastatic process (62, 63).…”

Hyperbaric oxygen and cancer: more complex than we expected

“…Metastasis is a complex process involving local cancer cell invasion, entry into the blood or lymph vessels, and repenetration and colonization at a distant site [3]. The integrity of vascular basement membrane (VBM) is crucial for the cancer cell invasion.…”