Past, Present, and Future of Oxygen in Cancer Research

Abstract

The first pathologists, oncologists, and medical physicists were aware that tumors were populated by an aberrant vasculature. The classic observations of Thomlinson and Gray in the 1950's established that O2 diffusion distances caused tumor to grow in cords. Tumor necrosis was observed surrounding a Krogh cylinder of viable tumor. That work helped explain earlier work by Warburg, who demonstrated a predisposition for tumors to favor anaerobic respiration, and it became the basis for 5 decades of subsequent research aimed at improving tumor oxygenation at the time of radiation. The role of O2 in modifying radiation response was attributed exclusively to the reactive free radicals that can be formed when O2 is present. These radicals produce approximately three-fold more irreparable double strand breaks in DNA. Subsequently it became clear that tumor had nutritional insufficiencies in addition to hypoxia. Ischemic regions are hypoglycemic, acidotic, have poor penetration of drugs, increased interstitial pressure, and altered immunological states. Ischemic regions can have intermittent reflow and associated redox stress. The relative impact of O2 compared to these associated phenomenon, and the degree to which hypoxia causes or follows these associated physiologic stresses, have been studied in detail. ISOTT scientists are responsible for much of the elucidation of the specific effects of O2, ADP/ATP ratios, hypoglycemia, and acidosis on tumor responses to radiation and hyperthermia. Many questions still remain.

The impact of O2 availability on human cancer

“…Even today, scientists lack an optimal method of direct tissue O 2 measurement that is noninvasive, precise, and quantitative; but this goal is clearly within reach (reviewed in 7 ). In the 1980's, in vivo polarographic measurements with electrodes and ex vivo cryospectrophotometric measurements of oxyhemoglobin provided some insight into the regional oxygenation status of tumors (reviewed in 8 ).…”

Classification of breast cancer precursors through exhaled breath

“…This can be understood in terms of cell biology: BC is promoted by the progressive accumulation of genetic and epigenetic changes in the breast cells [6], leading to cellular oxidative stress [7,8], and, thus, to the emission of BC-specific volatile biomarkers into the blood [9][10][11][12]. BC-promoting DNA methylation of certain genes has been observed even in benign lesions, indicating that epigenetic changes (very probably accompanied by measurable emission of volatile biomarkers) occur very early in the tumor genesis [3,6].…”

Effect of chronic intermittent hypoxia on biological behavior and hypoxia‐associated gene expression in lung cancer cells

“…The third case was characterized by cyclic periods of hypoxia and reoxygenation [Cooper et al, 2004;Weinmann et al, 2004Weinmann et al, , 2005Okunieff et al, 2005;Yao et al, 2005;Liu et al, 2006;Martinive et al, 2006;Dewhirst, 2007]. The previous studies showed that the major phenotypic shift associated with chronic hypoxia led to cellular resistance to chemotherapy, radiotherapy, promoting the tumor cells to become more invasive and metastatic.…”