TY - JOUR
T1 - The hypoxic tumor microenvironment regulates invasion of aggressive oral carcinoma cells
AU - Teppo, Susanna
AU - Sundquist, Elias
AU - Vered, Marilena
AU - Holappa, Heidi
AU - Parkkisenniemi, Juha
AU - Rinaldi, Tatiana
AU - Lehenkari, Petri
AU - Grenman, Reidar
AU - Dayan, Dan
AU - Risteli, Juha
AU - Salo, Tuula
AU - Nyberg, Pia
N1 - Funding Information: Johanna Myllyharju group is thanked for the LOX antibody and for the advice with the hypoxia workstation. Markku Santala is acknowledged for collection of the myoma tissues. Katja Koukkula, Eeva-Maija Kiljander, Maija-Leena Lehtonen, Sanna Juntunen, Maritta Harjapää, Merja Tyynismaa, Tanja Kuusisto and Erja Tomperi are thanked for excellent technical assistance. Mika Kihlström is acknowledged for the help with figure preparation. This study was financially supported by Academy of Finland, Finnish Cancer Organizations , Sigrid Juselius Foundation , Oulu University Hospital KEVO-support , and Finnish Dental Society Apollonia .
PY - 2013/2/15
Y1 - 2013/2/15
N2 - 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.
AB - 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.
KW - Carbonic anhydrase 9
KW - Hypoxia
KW - Invasion
KW - Lysyl oxidase
KW - Oral squamous cell carcinoma
KW - Tumor microenvironment
UR - http://www.scopus.com/inward/record.url?scp=84875497078&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.yexcr.2012.12.010
DO - https://doi.org/10.1016/j.yexcr.2012.12.010
M3 - مقالة
SN - 0014-4827
VL - 319
SP - 376
EP - 389
JO - Experimental Cell Research
JF - Experimental Cell Research
IS - 4
ER -
