Detection and Specific Targeting of Hypoxic Regions within Solid Tumors: Current Preclinical and Clinical Strategies

Abstract

Poor oxygenation of solid tumors is a major indicator of adverse prognosis after standard treatment, e.g. radiotherapy. This observation founded on intratumoral pO(2) electrode measurements has been supported more recently by studies of injected hypoxia markers (pimonidazole, EF5) or hypoxia-related proteins (hypoxia-inducible factor-1alpha, carbonic anhydrase IX) detected immunohistochemically. Alternative approaches include imaging of tumor hypoxia by nuclear medicine studies and the measurement of hypoxia-related proteins (osteopontin) in patient plasma. Low oxygen levels as found in tumors are rarely observed in normal tissues. The presence of hypoxic tumor cells is therefore regarded not only as an adverse prognostic factor but as an opportunity for tumor-specific treatment. Classic approaches to normalize tumor oxygenation involve the breathing of modified gas mixtures and pharmacologic modification of blood flow as in the "accelerated radiotherapy, carbogen, nicotinamide" (ARCON) scheme. Specific killing of hypoxic tumor cells can potentially be achieved by hypoxia-selective cytotoxins (model substance tirapazamine), which has shown promise in head and neck cancer. Direct targeting of hypoxia-related molecules such as hypoxia-inducible factor-1alpha, the central regulator of the hypoxic response in tumor cells, is an attractive approach currently tested in preclinical models. For clinical applications, the appropriate combination of hypoxia detection for patient selection with a hypoxia-specific treatment is essential. A therapeutic benefit has been suggested for the selection of patients by plasma osteopontin level and treatment with the hypoxic radiosensitizer nimorazole in addition to radiotherapy, for selection by F-misonidazole positron-emission tomography (PET) and treatment with tirapazamine in addition to chemoradiation and for selection by pimonidazole immunohistochemistry and ARCON treatment, all in head and neck cancer.

Metabolic response of lung cancer cells to radiation in a paper-based 3D cell culture system

“…The responsiveness of the cells in L6 to irradiation is unclear because the mean is smaller than about twice the standard error (i.e., 1.96 × standard error) for L6 of the non-irradiated stack (Table S-1a) [64]. These results are consistent with the response observed in solid tumors in vivo: cells in close proximity to blood vessels (i.e., < 200 µm) respond to radiation, and cells residing beyond this distance, which is believed to be a hypoxic environment, are likely insensitive to irradiation [32,[65][66][67].…”

Exosomal miR-135b shed from hypoxic multiple myeloma cells enhances angiogenesis by targeting factor-inhibiting HIF-1

“…Therefore, we established HR-MM cells, which can serve as a surrogate of therapy-resistant MM cells, because the biological effects of hypoxia on tumor cells are known to be resistant to anticancer chemotherapy and are known to increase the risk of tumor metastasis. [28][29][30] In the current study, we investigated the characteristics of exosome release in HR-MM cells. We first noted that the amount of exosomes from HR-MM cells was significantly greater than that of parental cells, and a subset of exosomal miRNA might work in a dose-dependent manner.…”

The Clinical Importance of Assessing Tumor Hypoxia: Relationship of Tumor Hypoxia to Prognosis and Therapeutic Opportunities

“…The presence of hypoxia in cancerous tissue was first reported by Thomlinson and Gray, who observed that hypoxic, yet viable, lung carcinoma rods were surrounded by a necrotic core caused by a tissue oxygen gradient (263). All types of solid tumors, especially malignant solid tumors, are subject to hypoxia, often exhibiting oxygenation levels measurably lower than their tissue of origin (Table 1) (7,27,124). Recurring tumors often exhibit a higher hypoxic fraction than primary tumors (258,280).…”