Relationship of hypoxia to metastatic ability in rodent tumours

Abstract

SummaryThe relationship between tumour oxygenation in vivo and metastatic potential was investigated in 2 rodent tumour models, KHT-C fibrosarcoma and SCC-VII squamous cell carcinoma. The oxygen status in these rodent tumours transplanted intramuscularly in syngeneic mice was measured using the Eppendorf pO 2 Histograph. The results indicate a considerable heterogeneity in oxygenation between individual tumours within each tumour cell line. At different tumour sizes, animals were killed and lung lobes were examined for macroscopic and microscopic lung metastases. In the KHT-C tumours, a significant increase in early pulmonary metastasis formation was observed in mice with hypoxic primary tumours. Hypoxic SCC-VII tumours did not give rise to enhanced lung metastasis formation despite oxygenation in a range similar to the KHT-C tumours. However, the overall metastasis incidence in the SCC-VII model was very low. The results obtained in the KHT-C model, which show that hypoxic tumours are more likely to metastasize, are in agreement with recent clinical data suggesting that a hypoxic environment might be implicated in metastatic ability of human tumours.

Nonlinear simulation of the effect of microenvironment on tumor growth

“…Indeed, a number of experimental studies have now shown that anti-angiogenic therapies may increase the tendency of tumors to fragment and invade surrounding host tissue. (e.g., Sakamoto (1987), Rubinstein et al (2000), DeJaeger et al (2001), E. Rofstad and Halso (2002), Seftor et al (2002), Lamszus et al (2003), and Bello et al (2004).) Conversely, we found that increasing the nutrient levels in the microenvironment leads to greater morphological stability and increased compactness of the tumor, thereby rendering the tumors more resectable.…”

Nonlinear Modeling and Simulation of Tumor Growth

“…A number of experimental studies have recently shown that anti-angiogenic therapies may have this result [180,177,61,173,185,122,24]. Conversely, we found that increasing nutrient levels leads to greater morphological stability and increased tumor compactness, thereby rendering some tumors more resectable.…”

“…This includes the application of mathematical and empirical methods to quantify the competition between cell substrate gradient-related pro-invasion phenomena and molecular forces that govern proliferation and taxis, and forces opposing invasion through cell adhesion. The latter, under normoxic conditions, often enforce compact non-infiltrative tumor morphology while local oxygen gradients promote invasion [190,156,185,120,160,122,24,177,173,174,61,55,74,135]. Interactions between cellular proliferation and adhesion and other phenotypic properties may be reflected in both the surface characteristics, e.g., stability, of the tumor-host interface and the growth characteristics of tumors [59,55,74,87,135].…”

“…Three-dimensional tissue morphology, cell phenotype, and molecular phenomena are intricately coupled; they influence cancer invasion potential by controlling tumor-cell proliferation and migration [78,187,198]. Hypoxia [88,210,186,70,91], acidosis [91,199,96], and associated diffusion gradients, caused by heterogeneous delivery of oxygen and nutrients and removal of metabolites [104,103] due to highly disorganized microvasculature [92,106] and often exacerbated by therapy (e.g., anti-angiogenic [160,177]), can induce heterogeneous spatial distribution and invasiveness of tumor cells through a variety of molecular [175,209,208,44,165,173,145,118,28,29,190,156,185,120,122,24,160,177,174,61] and tissue-scale [59,127,72] mechanisms corresponding to different tissue-scale invasive patterns [78,164,194,167,<...>…”

Tumor Vasculature: a Target for Anticancer Therapies

“…Indeed, it is now established that the presence of oxygen-defi cient or hypoxic cells can not only lead to therapeutic resistance in preclinical tumor models but also have a detrimental effect on the ability to control human malignancies treated with curative intent (Hoeckel et al, 1993;Nordsmark, Overgaard and Overgaard 1996;Brizel et al, 1999, Brown andGiaccia, 1998;Horsman and Overgaard, 2002). Importantly, physiological pressures exerted by the tumor microenvironments also contribute to processes that favor malignant progression (Young, Marshall and Hill, 1988;Hill, 1990;Giaccia, 1996), oncogenesis (Giaccia, 1996;Graeber et al, 1996) and potential for metastatic spread (Young, Marshall and Hill, 1988;Hill, 1990;De Jaeger, Kavanagh and Hill, 2001;Brizel et al, 1996).…”