title: The hypoxic tumor microenvironment regulates invasion of aggressive oral carcinoma cells.
abstract: Invasion is an important hallmark of cancer involving interactions between the tumor microenvironment and the cancer cells. Hypoxia, low oxygen level, is related to increased invasion and metastasis in many cancers. The aim was to elucidate the effect of hypoxia on invasion of oral squamous cell carcinoma cells (OSCCs), and the applicability of a novel 3-dimentional myoma organotypic invasion model in hypoxia experiments. OSCC cell lines (primary oral carcinoma derived cells UT-SCC-43A, recurrent oral carcinoma cells UT-SCC-43B and aggressive tongue carcinoma cells HSC-3) were studied for their migration and invasion capabilities under normoxia, hypoxia, and in the presence a hypoxia-mimicker cobalt chloride. As expected, the recurrent UT-SCC-43B cells were significantly more aggressive than the primary tumor derived cells. In contrast to tongue carcinoma HSC-3 cells, they only mildly responded to hypoxia in the migration or invasion assays, indicating a cell line specific response of hypoxia on the invasive potential. The modification of the organotypic human tissue-derived matrix via the removal of various yet unidentified soluble factors by rinsing the tissue resulting in stripped matrix substantially changed the invasion pattern of HSC-3 cells and the outcomes of hypoxic treatments. Only in the stripped tissue hypoxia significantly increased invasion, whereas in native intact tissue the induced invasion was not observed. This demonstrates the importance of the soluble factors to the invasion pattern and to the hypoxia response. A metastasis and poor prognosis marker, hypoxia-regulated lysyl oxidase (LOX), was present in the myoma tissue, but could be removed by rinsing. The inhibition of LOX resulted in a decrease in invasion area, but only very mildly in invasion depth. Thus, it may have a role in the modulation of the invasion pattern. Another hypoxia-related poor prognosis marker carbonic anhydrase 9 (CAIX) was induced in HSC-3 cells both by the hypoxic exposure and interestingly in invading HSC-3 cells inside the tissue even in normoxic conditions. In conclusion, this suggests that the intact myoma organotypic model offers optimally hypoxic surroundings, thus being an excellent human tumor microenvironment mimicker.
authors.affiliation: Department of Diagnostics and Oral Medicine, Institute of Dentistry, University of Oulu, Finland.
authors.forename: Susanna
authors.initials: S
authors.lastname: Teppo
authors.forename: Elias
authors.initials: E
authors.lastname: Sundquist
authors.forename: Marilena
authors.initials: M
authors.lastname: Vered
authors.forename: Heidi
authors.initials: H
authors.lastname: Holappa
authors.forename: Juha
authors.initials: J
authors.lastname: Parkkisenniemi
authors.forename: Tatiana
authors.initials: T
authors.lastname: Rinaldi
authors.forename: Petri
authors.initials: P
authors.lastname: Lehenkari
authors.forename: Reidar
authors.initials: R
authors.lastname: Grenman
authors.forename: Dan
authors.initials: D
authors.lastname: Dayan
authors.forename: Juha
authors.initials: J
authors.lastname: Risteli
authors.forename: Tuula
authors.initials: T
authors.lastname: Salo
authors.forename: Pia
authors.initials: P
authors.lastname: Nyberg
mesh_terms: D000368:Aged; D000629:Aminopropionitrile / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology*; D054443:Cell Migration Assays; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D000860:Hypoxia / Q000150:complications / Q000473:pathology*; D007889:Leiomyoma / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000378:metabolism / Q000473:pathology*; D009361:Neoplasm Invasiveness; D008249:Protein-Lysine 6-Oxidase / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment / Q000187:drug effects / Q000502:physiology*; D014594:Uterine Neoplasms / Q000378:metabolism / Q000473:pathology; D014945:Wound Healing
chemical_list: D004791:Enzyme Inhibitors; D000629:Aminopropionitrile; D008249:Protein-Lysine 6-Oxidase