Biology Reference
In-Depth Information
7.10 Extravasation: Breaching the Basement Membrane
Following Transendothelial Migration
After arrest at specific sites on subluminal surfaces of hematogenous or lymphatic
vessels, tumor cells have to first migrate through the endothelial cell barrier and
then penetrate underlying vascular BM in a process long referred to as extravasa-
tion. There is no consensus as to whether extravasation is a rate-limiting step in the
metastatic cascade since it is a highly efficient process when evaluated in experi-
mental metastasis models where tumor cells are injected directly into the circula-
tion (Chambers et al.
1992
; Koop et al.
1995
).
A few models have been introduced to study extravasation in vitro allowing for
detailed mechanistic analysis of critical events involved in this process, i.e., inter-
action of tumor cells with the endothelial layer, transendothelial migration, and
invasion of the matrix underlying the endothelium. In a Transwell model, down-
regulation of MMP-1 in conjunction with one or more genes significantly inhibited
transendothelial migration of breast carcinoma cells (Gupta et al.
2007
; Kim et al.
2009
). Combined with confocal microscopy, 3D extravasation models demonstrate
that transendothelial migration is complete within a few hours after tumor cells
attach to the endothelium and involves pseudopodia formation (Qi et al.
2005
,
2006
). Therefore, a contribution of invadopodia-associated MMPs, e.g., MT1-
MMP, in the degradation of vascular BM might be anticipated. During transen-
dothelial migration in vitro, tumor cells were observed to irreversibly damage
endothelium at the site of migration (Brandt et al.
2005
). Whether the integrity of
the layer, and possibly of the underlying matrix, were breached in an MMP-
dependent manner was not addressed in these studies, but the finding of structural
damage to the endothelium might suggest a mechanism for the efficient collective
extravasation of tumor cell cohorts at an individual point of exit.
Tissue specifics of endothelia and endothelial BMs in distant sites may require
differential expression of molecules which would in one or another way assist in
extravasation at different secondary tissues or organs. The structure of blood vessel
or lymphatic endothelia in different organs varies significantly with regard to their
level of fenestration (Strell and Entschladen
2008
) or continuity of the BM (Pepper
and Skobe
2003
), which might explain different rates of colonization by extravasat-
ing cells. Thus, discontinuous endothelium in the liver sinusoids with large gaps
that expose the underlying ECM (Aird
2007a
,
b
) might explain high levels of liver
colonization observed in some metastatic cancers and experimental metastasis
model systems (Kuo et al.
1995
; Kobayashi et al.
1998
; Conn et al.
2009
; Deryugina
et al.
2009
), while incomplete BM of lymphatic capillaries might explain high
propensity of certain aggressive tumor cells for lymph node metastases and lym-
phatic route of dissemination.
Following transendothelial passage, the MMPs must proteolytically degrade the
endothelial BM, and in principle, these MMPs might functionally overlap with
those participating in the degradation of vascular BM proteins during intravasation.
Thus, type IV collagen degradation indicating the breaching of vascular BM was
