Fluctuating and Diffusion-Limited Hypoxia in Hypoxia-Induced Metastasis

Abstract

Purpose: Most tumors develop regions with hypoxic cells during growth, owing to permanent limitations in oxygen diffusion (chronic or diffusion-limited hypoxia) and/or transient limitations in blood perfusion (acute or fluctuating hypoxia).The aim of this study was to investigate the relative significance of chronic and acute hypoxia in the development of metastatic disease. Experimental Design: D-12 and R-18 human melanoma xenografts were used as models of human cancer. D-12 tumors metastasize to the lungs, whereas R-18 tumors develop lymph node metastases. Fraction of radiobiologically hypoxic cells (HF Rad ) was measured in individual primary tumors by using a radiobiological assay based on the paired survival curve method. Fraction of immunohistochemically hypoxic cells (HF Imm ) was assessed in the same tumors by using a pimonidazole-based immunohistochemical assay optimized with respect to achieving selective staining of chronically hypoxic cells. HF Imm and the difference between HF Rad and HF Imm , HF Rad À HF Imm , were verified to be adequate variables for fractionof chronically hypoxic cells and fractionof acutely hypoxic cells, respectively. Results: Chronic as well as acute hypoxia were found to promote spontaneous metastasis of D-12 and R-18 tumors. Acute hypoxia influenced metastasis to a greater extent than chronic hypoxia, partly because the fraction of acutely hypoxic cells was larger than the fraction of chronically hypoxic cells in most tumors and partly because acutely hypoxic cells showed a higher metastatic potential than chronically hypoxic cells. Conclusions: It may be beneficial to focus on fluctuating hypoxia rather than diffusion-limited hypoxia when searching for hypoxia-related prognostic variables and predictive assays.

Low-dose metronomic cyclophosphamide treatment mediates ischemia-dependent K-ras mutation in colorectal carcinoma xenografts

“…For instance, there are conflicting data regarding the influence of extensive vascularization on tumor progression (Koukourakis et al, 2000), and intriguing evidence that antiangiogenic therapy may paradoxically enhance the efficacy of standard cytotoxic approaches (Kerbel, 2006). Tumor progression may be promoted by both chronic (diffusion-limited) as well as acute (fluctuating) tumor hypoxia (Janssen et al, 2005;Rofstad et al, 2007), and antiangiogenic therapy increases the proportion of cells undergoing both types of hypoxia (Rofstad et al, 2007). Currently, intervention with antiangiogenic agents is performed in relatively late stages of disease, where there are more angiogenic and survival pathways involved and manipulations of any single factor (such as inhibition of vascular endothelial growth factor) likely become less critical for cancer progression Kerbel and Folkman, 2002;Franco et al, 2006).…”

Dynamic contrast-enhanced MRI of the microenvironment of pancreatic adenocarcinoma xenografts

“…Pimonidazole [1-[(2-hydroxy-3-piperidinyl)-propyl]-2-nitroimidazole], injected as described previously [29], was used as a marker of tumor hypoxia, and CD31 was used as a marker of endothelial cells. An anti-pimonidazole rabbit polyclonal antibody (Professor Raleigh, University of North Carolina, NC, USA) or an antimouse CD31 rabbit polyclonal antibody (Abcam, Cambridge, UK) was used as primary antibody.…”

“…Microvessels were defined and scored manually as described by Weidner [30]. Fraction of hypoxic tissue was assessed by image analysis [29] and was defined as the area fraction of the viable tissue showing positive pimonidazole staining.…”

Chronic Hypoxia Decreases Synthesis of Homologous Recombination Proteins to Offset Chemoresistance and Radioresistance

“…Hypoxic tumor cells can be locally and systemically aggressive with a decreased sensitivity to apoptotic and other cell death signals, increased angiogenesis, increased proliferation, and an increased capacity for systemic metastasis (4)(5)(6). Experimental and spontaneous metastatic capacity can be increased when tumor cells are subjected to hypoxia and can be secondary to genetic instability (6)(7)(8). Anoxic cells can also be more chemoresistant and radioresistant than oxic cells.…”