Vascular architecture and hypoxic profiles in human head and neck squamous cell carcinomas

Abstract

The relevance of blood flow for the outcome of radiation treatments was already described by Schwartz in 1909. He noticed that skin reactions were less severe when the radium applicator was firmly pressed to the skin. It was Cramer in 1935 who gave the first suggestion of an 'oxygen effect'. He found that mouse mammary tumours with a well developed stroma and vascular network were more radiosensitive than tumours with a more delicate stromal component. He suggested that the radiosensitive tumours had a better blood supply and, consequently, were better oxygenated. Later, Gray et al (1953) established the importance of tumour oxygenation for radiotherapy.The tumour micro-environment is a key factor in tumour biology and has great impact on clinical radiotherapy as well as other cancer treatments. Single parameters such as polarographic pO 2 measurements and microvascular density have been demonstrated to be prognostic indicators in a variety of tumour types, including carcinomas of the head and neck (Gatenby et al, 1987;Dray et al, 1995;Zätterström et al, 1995;Jenssen et al, 1996;Nordsmark et al, 1996;Brizel et al, 1997). However, considering the complexity of the micro-environmental system, it is unlikely that a single parameter can reliably predict treatment outcome on an individual basis. Multiple parameter analysis will be necessary to acquire a better understanding of the tumour micro-environment and to obtain a 'predictive profile' which can guide the clinician in the selection of patients for new treatment strategies.A computerized image analysis system for multi-parameter analysis has been developed in our institute (Rijken et al, 1995). The method involves computer controlled microscopic scanning of immunohistochemically stained tissue sections. It allows quantitative and simultaneous analysis of vascular parameters, oxygenation status and proliferation parameters. We have recently published our experience with this method in xenografted human tumours (Bussink et al, 1998(Bussink et al, , 1999.We now apply this method also to tumour biopsies from patients with squamous cell carcinomas of the head and neck. Before a biopsy was taken, the patients were injected with Hypoxyprobe-1 (pimonidazole hydrochloride) as a hypoxia marker. Pimonidazole can easily be dissolved in saline, has a low toxicity, and an efficient tumour uptake. So far pimonidazole has proven to be an effective hypoxia marker for human tumours of the cervix and head and neck (Kennedy et al, 1997;Raleigh et al, 1998;. In the present study we report the results of the analysis of biopsy material from 21 patients with squamous cell carcinoma of the head and neck. MATERIALS AND METHODS PatientsPatients with primary laryngeal, oropharyngeal (stage III-IV) or hypopharyngeal (stage II-IV) squamous cell carcinomas were Summary Tumour oxygenation and vasculature are determinants for radiation treatment outcome and prognosis in patients with squamous cell carcinomas of the head and neck. In this study we visualized and quantified these factors which m...

Patterns and Levels of Hypoxia in Head and Neck Squamous Cell Carcinomas and Their Relationship to Patient Outcome

“…Type 1 binding pattern is most similar to EF5 binding in sarcomas and brain tumors 24,25 and Type 2 binding is most reminiscent of the EF5 binding patterns described in normal human skin 30 . Using pimonidazole, similar patterns of binding have been reported 45,46 . These binding patterns for pimonidazole have been described in cervix cancer, but the classified patterns are on a larger scale (mm) than we discuss herein (μm).…”

Dynamics of Hypoxia, Proliferation and Apoptosis after Irradiation in a Murine Tumor Model

“…Tumor cell proliferation is generally decreasing at increasing distances from blood vessels. Frequently tumor cells outgrow the vascular supply, resulting in tumor cell hypoxia, which is often found at greater distances from blood vessels or surrounding regions of tumor necrosis (4)(5)(6)(7)(8). In addition, fluctuations in tumor blood flow result in different gradients of oxygen and nutrients (9,10).…”

“…Dynamic processes in the tumor microenvironment can be visualized with immunohistochemical staining of endogenous and exogenous markers, which can be analyzed in relation to tumor vasculature with microregional imaging techniques (4,7,(32)(33)(34). Several exogenous markers of hypoxia such as pimonidazole, EF5 and CCI-103F are available (7,8,32,35).…”

“…Several exogenous markers of hypoxia such as pimonidazole, EF5 and CCI-103F are available (7,8,32,35). With consecutive injection of two hypoxic cell markers, pimonidazole and CCI-103F, treatment-induced changes in hypoxia can be measured, allowing each tumor to serve as its own control (36)(37)(38).…”

Dynamics of Tumor Hypoxia Measured with Bioreductive Hypoxic Cell Markers

“…The labeled tumor cells are generally found at greater distances from blood vessels, with increasing staining intensities along gradients of decreasing oxygen tensions. The most intensely stained cells are often located in the perinecrotic regions (25,(31)(32)(33)(34)(35).…”