Tumour hypoxia and vascular density as predictors of metastasis in squamous cell carcinoma of the uterine cervix

Abstract

Summary Some clinical studies involving several histological types of cancer have suggested that high vascular density in the primary tumour promotes metastasis. Other studies have suggested that a high incidence of metastases is associated with low oxygen tension in the primary tumour. The purpose of the study reported here was to search for correlations between incidence of metastases and oxygen tension or vascular density in the same population of patients. Thirty-eight consecutive patients with squamous cell carcinoma of the uterine cervix were included in a prospective study. Pelvic, iliac and retroperitoneal lymph node metastases were detected by magnetic resonance imaging at the time of initial diagnosis. Oxygen tension was measured polarographically using the Eppendorf P02 Histograph 6650. Vascular density was determined by histological examination of tumour biopsies. The primary tumours of the patients with metastases (n = 19) were more poorly oxygenated than those of the patients without metastases (n = 19). Thus, the fractions of the P02 readings resulting in values below 5 mmHg and 10 mmHg were significantly higher for the former group of patients than for the latter (P = 0.03 and 0.02 respectively). In contrast, the vascular density of the primary tumour was not significantly different for the two groups of patients. The present study suggests that a high incidence of metastases in squamous cell carcinoma of the uterine cervix is associated with poor oxygenation of the primary tumour and not with a high vascular density.

How to overcome (and exploit) tumor hypoxia for targeted gene therapy

“…To facilitate tumor cell detachment, migration and invasion, hypoxia can down-regulate cell adhesion molecules such as integrins (Hasan et al, 1998), and upregulate the urokinase-type plasminogen activator receptor (uPAR; Rofstad et al, 2002) and the autocrine motility factor (AMF; Niizeki et al, 2002). An association between primary tumor oxygenation and the likelihood of distant metastasis has been reported in clinical studies involving patients with high-grade soft tissue sarcoma (Brizel et al, 1996) and advanced squamous cell carcinoma of the uterine cervix (Sundfor et al, 1998;Pitson et al, 2001;Fyles et al, 2002). Also, a positive correlation has been observed between tumor lactate concentration and the presence of metastatic deposits in cervix and head and neck squamous cell carcinomas (Rofstad, 2000;Brizel et al, 2001), while ATP and glucose concentration did not show significant correlation (Rofstad, 2000).…”

“…Hypoxia-driven cellular modifications may contribute to this poor prognostic outlook, giving rise to more aggressive locoregional disease, invasive capacity, and angiogenesis ( Fig. 1; Brizel et al, 1996;Sundfor et al, 1998;Graham et al, 1999;Hockel et al, 1999;Walenta et al, 2000).…”

“…However, clinical data are conflicting. Squamous cell carcinomas of the uterine cervix, characterized by pronounced hypoxia (Sundfor et al, 1998) and low apoptotic index (Hockel et al, 1999), showed a high probability for lymphatic spread and recurrence, despite adjuvant treatment with radiation or chemotherapy in addition to radical surgery (Hockel et al, 1999). Also, in cervix carcinomas a significant correlation between hypoxia and functionally impaired p53 was demonstrated (Haensgen et al, 2001).…”

Relationship of hypoxia to metastatic ability in rodent tumours

“…Presently, the determination of oxygen concentration with polarographic electrodes is the only method of measuring hypoxia that has been extensively studied in patients. Decreased tumour oxygenation, as measured with polarographic electrodes, has been reported to be a predictor of poor local response following radiotherapy in cervix cancer (Höckel et al, 1993;Fyles et al, 1998;Sundfør et al, 1998;Knocke et al, 1999;Lyng et al, 2000) head and neck cancer (Gatenby et al, 1988;Nordsmark et al, 1996;Brizel et al, 1997) and soft tissue sarcoma (Brizel et al, 1996). Recently, clinical data have emerged suggesting that hypoxia adversely affects locoregional control of cervical cancer, irrespective whether the initial treatment modality is radiotherapy or surgery (Höckel et al, 1996).…”

Hypoxia-induced treatment failure in advanced squamous cell carcinoma of the uterine cervix is primarily due to hypoxia-induced radiation resistance rather than hypoxia-induced metastasis

“…Several studies of advanced cervix carcinoma have demonstrated a positive association between poor outcome of radiation therapy and poor oxygenation of the primary tumour, measured with the Eppendorf pO 2 histograph prior to treatment (Höckel et al, 1993;Fyles et al, 1998a;1998b). The worse treatment outcome of the patients with the most hypoxic tumours could be related to the classical oxygen effect (Bush, 1986;Overgaard et al, 1989) or to the development of metastases associated with hypoxia (Höckel et al, 1996;Sundfør et al, 1998).…”