Blood flow in human tumors during hyperthermia therapy: Demonstration of vasoregulation and an applicable physiological model

Hypoxia within the tumor microenvironment is correlated with poor treatment outcome after radiation and chemotherapy, and with decreased overall survival in cancer patients. Several molecular mechanisms by which hypoxia supports tumor growth and interferes with effective radiation and chemotherapies are now well established. However, several new lines of investigation are pointing to yet another ominous outcome of hypoxia in the tumor microenvironment: suppression of anti-tumor immune effector cells and enhancement of tumor escape from immune surveillance. This review summarizes this important information, and highlights mechanistic data by which hypoxia incapacitates several different types of immune effector cells, enhances the activity of immunosuppressive cells and provides new avenues which help “blind” immune cells to the presence of tumor cells. Finally, we discuss data which indicates that mild thermal therapy, through its physiologically-regulated ability to alter vascular perfusion and oxygen tensions within the tumor microenvironment, as well as its ability to enhance the function of some of the same immune effector activities that are inhibited by hypoxia,, could be used to rapidly and safely release the tight grip of hypoxia in the tumor microenvironment thereby reducing barriers to more effective immune-based therapies.

Section: Hyperthermia-induced Changes In Tumor Oxygenation and Vasculsupporting

confidence: 87%

Hypoxia-driven immunosuppression: A new reason to use thermal therapy in the treatment of cancer?

Lee

Mace

Repasky

2010

“…Langendijk et al 1988 (23 patients, up to five treatments each) reported that blood flow typically did not change during the stationary part of a hyperthermia session. Olch et al 1983 reported that seven out of nine tumours demonstrated an increase in blood flow in response to hyperthermia. Thus, the trends in the present study agree well with those of these other clinical invistigations showing either no change or an increased tumour perfusion occurring during hyperthermia.…”

Section: Discussionmentioning

confidence: 98%

“…The human tumours studied in those investigations were treated with externally applied microwaves. Methods used to monitor blood perfusion related quantities in human tumour studies have included '33Xenon-clearance (Olch et al 1983), thermoclearance (Waterman et al. 1987, 1991) steady state temperatures (Lagendijk et al 1988), and laser Doppler (Acker etal.…”

Section: Introductionmentioning

confidence: 99%

Patterns of changes of tumour temperatures during clinical hyperthermia: Implications for treatment planning, evaluation and control

Anhalt

Hynynen

Roemer

1995

The patterns of changes in tumour temperatures were studied at selected times throughout 104 hyperthermia sessions. Temperature change patterns were analysed in the context of the known patterns of change of the applied power. First, of 69 extracranial treatments analysed, 74% indicated relatively flat temperatures at constant applied power during a major portion of the treatment, thereby indicating that during that time there were no major changes in any of the physical or physiological tissue parameters which contribute to the ability of the tumour tissue to remove energy (Pattern 1). Second, after reaching an initial steady state, approximately 14% of these extracranial treatments showed either steadily decreasing temperatures at constant power, or constant temperatures at steadily increasing applied power, thereby indicating that the tumour's ability to remove energy was steadily increasing in time following the initial steady state (Pattern 2). Finally, after reaching an initial steady state, the remaining 12% of these treatments showed a pronounced decrease in temperature occurring about 10-20 min into the treatment followed by increasing temperatures or levelling off of temperatures at a higher value than the temperature minimum that had occurred, all at constant applied power (Pattern 3). Of 35 brain treatments analysed, 80% followed Pattern 1, 14% followed Pattern 2, and 6% followed Pattern 3. Intratumoral heterogeneity was evident in some cases with approximately 44% of all treatments having at least one individual temperature sensor change in a manner that did not follow the average direction of change when all sensors were combined. For seven patients with permanent probes, the patterns of change presented in the first treatments were also observed during six out of seven of the second treatments. In addition, three out of the five patients who had an evaluable third treatment showed a pattern of change during that third treatment that was similar to the pattern observed in both treatment one and treatment two.

“…Tumour thermotolerance or vascular thermotolerance, an induced resistance of the tumour to hyperthermia, is a potentially powerful and clinically pertinent by-product observed in patients receiving multiple hyperthermia treatments [28]. Thus far, the basic concept of vascular thermotolerance has been characterised as a markedly increased blood flow response of the tumour to a second hyperthermia exposure compared to the response to a single thermal dose, even at temperatures that would normally cause vascular damage [6, 7].…”

Section: Discussionmentioning

confidence: 99%

Tumour thermotolerance, a physiological phenomenon involving vessel normalisation

Dings

Loren

Zhang

et al. 2011

The purpose of this study was to delineate the mechanisms by which stromal components of cancer may induce tumour thermotolerance and exploit alterations in stromal and tumour physiology to enhance radiation therapy. The vascular thermoresponse was monitored by daily one-hour 41.5°C heatings in two murine solid tumour models, SCK murine mammary carcinoma and B16F10 melanoma. A transient increase was seen in overall tumour oxygenation for 2–3 days, followed by a progressive decline in tumour pO2 upon continued daily heatings. Vascular thermotolerance was further studied by treating tumours with different heating strategies, i.e. (1) a single 60 min 41.5°C treatment; (2) two consecutive daily treatments of 41.5°C for 60 min; (3) a single 60 min 43°C treatment or (4) two days of 41.5°C for 60 min followed by treatment with 43°C for 60 min on the third day. Pre-heating tumours with mild temperature hyperthermia induced vascular thermotolerance, which was accompanied by evidence of vessel normalisation, i.e. a decrease in microvessel density and an increase in pericyte coverage. Rational scheduling of fractionated radiation during heat-induced increases in tumour oxygen levels rendered a significantly greater, synergistic, tumour growth inhibition. In vitro clonogenic survival responses of the individual cell types associated (endothelial cells, fibroblasts, pericytes and tumour cells) indicated only a direct cellular thermotolerance in endothelial cells. Overall, this suggests that tumour thermotolerance is a physiological phenomenon mediated through improvement of functional vasculature.