Tumour angiogenesis and metastasis

I've read up on tumour angiogenesis, and have learned that tumour vasculature is really a meshwork of unorganized tubular interconnections (Fukamura & Jain 2007). These vessels have varying diameters, numerous trifurcations, saccules, and they often don't have a continuous endothelial layer or basement membrane (Figure 1).

FIGURE 1. Normal (left) vs. cancerous (right) vessels.

Because of the disorganization of endothelium, tumour vessels have large fenestrations that may be up to 2 um in diameter (Figure 2). This, on top of numerous pores, makes these vessels very leaky. As a result, cancer cells can easily intravasate into these vessels because of the loose extracellular matrix, and the thin or non-continuous vessel walls. With cancer, the process of intravasation - which is normally an active process of MMPs and cytoskeletal rearrangement - may become a passive procedure where tumour growth extrudes and sloughs off tumour cells into the compressed vessels (Bockhorn et al. 2007). This occurs at regions where endothelial cells are missing, where tumour cells act as the lumen wall (Figure 3).

FIGURE 2.

As seen in Figure 2, the endothelial layer exhibits numerous pores and intercellular fenestrations, and endothelial cells often form long cellular processes (Hashizume et al. 2000). As mentioned in the previous paragraph, tumour vessels are easily compressed by the unhindered growth of tumours, resulting in their tortuous and irregular shapes seen in Figure 3. Blood flow in these vessels are significantly lower than their normal counterparts. This allows for pooling of blood. Also, the irregularity of the blood supply results in numerous regions of necrosis.

FIGURE 3. Cancer tastes like watermelon!

Cancer cells are continuously shed into the circulatory system. But, few ever implant successfully into the metastatic site. From the literature I've read thus far, I'm under the impression that while tumour cells travel as aggregates, they may still intravaste individually. I would imagine that the chances of survival singularly are slim, however. What I found interesting is that platelets may aid cancer cells in evading the host immune cells in circulation (Palumbo et al. 2005); fibrin may prevent NK cells from recognizing the circulating tumour embolus.

As for extravasation at the metastatic site, in metaphyseal bone... Sinusoidal vessels predominate within spongey bone. They are large vessels with flow at 30-folds lower than that of arteries (Bussard et al. 2008). Similar to tumour vasculature, sinusoid endothelial cells interdigitate to create a highly-fenestrated and discontinuous layer. The basement membrane and the adventitial layer, which consists of phagocytic cells, are both discontinuous as well.

As of yet, again I have not found solid evidence that migrated cancer cells need to immediately break down bone extracellular matrix to implant, although evidence shows that they are functionally able to (Yoneda et al. 1997). MMPs may be used to break through the vessel walls and what little extracellular matrix there is. Once expose to bone, cancer cells adhere to the bone surface by use of adhesion molecules such as VLA-4 and ICAM-1 (Bussard et al. 2008). After this step, growth may begin.

A revisit to my storyboard idea "The Metastacizing Cell" will be necessary.