Dear colleagues, I've browsed a lot of papers and encountered the fact that when the both primary and metastatic tumors are of interest for researchers and when the xenograft model is involved, metastasis in achieved by the direct tail vein injection of the cell suspension. Yet, xenograft tumor itself seems to be fully capable of forming metastases. So the question is - do xenograft tumors spread metastases? Or does it take too long for them to do it, so it is impossible in most investigations to detect them, as establishing metastatic tumors is surely challenging.
Dear Peter,
I guess that it really depends on the cell line that one is choosing for the establishment of the xenograft model. There are highly metastatic lines as well as low ones. There are highly proliferative cells and others that require months before they develop into full tumor mass. One can speed up things by co-injecting cells with matrigel for example. During the engraftment time, injected cells highjack the surrounding tissue and initiate mechanisms to support the growth of the tumor itself. One of them is certainly angiogenesis, that not only will provide nutrients for the metabolic needs of the cells, but also function as an escape route for cells that are shedding from the primary tumor. Once in circulation, tumor cells are able to extravasate, colonize new organs and potentially give rise to metastasis.
Xenograft tumors metastasize rather well especially when the cell lines you use are highly metastatic. MDA MB 231 metastasize following tail vein injection or after mamary fat transplantation
MDA MB 231 mamary tumor cells metastasize mainly in marrow and B16 melanoma cells metastasize mainly in lungs. It could be expontaneous or, as Pichas has indicated, you can speed up the process by injecting these cells trough the tail vein.
Apart from a rare one, HTX and PDX transplanted subcutaneously do not metastasise, selected HTX transplanted orthotopically metastasise and as said in previous comments you can tail vein injections of HTX cell suspensions to obtain metastases.
As Matteo Bocci said, it will depend on the cell lines that you´re using to. Moreover, the number of cells that you´ll inject subcutaneously could also influence this mechanism. Of course it´s "easier" that you get metastasis if you inject them directly on the tail vein (cells will be circulating-systemic circulation) but you can also find metastasis using xenotransplantation. it´s important to say that firstly you have to choose the "right" cells, the "right" number, the suitable procedure (maybe inject them using matrigel, for example) and then verify (on the literature) wich organs are more propitious to metastasize with that specific cell type. Hope help you.
Most animal protocols require that animals be sacrificed once a xenograft tumor (such as a subcu tumor) reaches around 2 cm in diameter or starts bleeding or causing the animal distress. Because sometimes this would require an animal to be sacrificed before the onset of metastasis, tail vein injection may be a preferable way to study metastasis. Depending on the cell line, intravasation (getting into the bloodstream) may be the rate-limiting step of metastasis, rather than extravasation.
To my humble opinion, it all comes down to the tumour microenvironment, be it due to the orthotopic implant or to the higher ease of a particular animal model (animal+cell line) to develop vasculature/stroma. The pathophysiology plays a key role in metastasis. Depending on the variables you're interested in, tail-vein injection might bias your results, thus the cells you are injecting might not be in the "metastasis-mode", or in other words might not be cancer-initiating cells (R. Weinberg(from MIT)'s work). Also, the work of M. Bissell from UC Berkley is very inspiring.
Here's a paper with a bunch of cell lines and their pathophysiologies:
Smith, Neil R., et al. "Tumor stromal architecture can define the intrinsic tumor response to VEGF-targeted therapy." Clinical Cancer Research 19.24 (2013): 6943-6956.
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