THE MICROENVIRONMENT IS ESSENTIAL FOR OTSCC PROGRESSION, ACTA UNIVERSITATIS OULUENSIS D Medica 1390
|Kustantaja:||Oulun yliopisto|| |
|Painos:||Osajulkaisuväitöskirjan yhteenveto-osa|| |
|Sijainti:||Print Tietotalo|| |
|Tekijät:||ALAHUHTA ILKKA|| |
The tumor microenvironment (TME) is critically important for tumor development. The
microenvironment consists of fibroblasts, endothelial and immune cells as well as extracellular
matrix (ECM), proteases and various other soluble factors produced by the cells. It is challenging
to develop methods that appropriately mimic the human microenvironment, but this effort is
essential in order to reliably elucidate the properties of potential anti-tumor drugs. The aim of this
study was to create new 3D organotypic invasion models based on human tissue that would be
used to study the effects of the anti-angiogenic molecules arresten and endostatin on tongue
squamous carcinoma cells.
The classic way to study cancer invasion has been to use a collagen invasion model that is
created by mixing rat type I collagen, matrix produced by mouse EHS tumor cells and human
fibroblasts. Our research group has developed a novel human myoma tissue based invasion model,
which is composed of several different cell types and molecules that are normally present in the
human TME. We show how this model is suitable for invasion studies, not only for oral cancer,
but for other invasive cell lines as well.
There are several matrix-derived fragments that have been shown to possess anti-angiogenic
activity. Arresten is a 26 kDa fragment that is cleaved from type IV collagen and is known to
inhibit angiogenesis, the formation of new capillaries and tumor growth in vivo. However, its
effect on the tumor microenvironment in addition to endothelial cells has not been studied. We
show that arresten also directly affects oral cancer cells by decreasing their migration and invasion
as well as tumor size, invasion and angiogenesis in in vivo mouse xenografts.
Another inhibitor of angiogenesis, endostatin, is cleaved from type XVIII collagen. It has been
shown to suppress angiogenesis and tumor growth without toxicity or side effects in mouse
models. Our studies show that endostatin directly affects tongue squamous carcinoma cells by
reducing their invasion and spreading in organotypic 3D assays and mouse tumor models.
In summary, arresten and endostatin are anti-angiogenic as well as anti-invasive molecules and
therefore potential cancer drugs. They seem to have a direct effect on carcinoma cells making the
cells less invasive. The myoma model allows us to study the effects of anti-cancer molecules with
a new prospective.