Abstract
For more than a century oxygen has been known to be one of the most powerful radiosensitizers. However, despite decades of preclinical and clinical research aimed at overcoming tumor hypoxia, little clinical progress has been made so far. Ionizing radiation damages DNA through generation of free radicals. In the presence of oxygen these lesions are chemically modified, and thus harder to repair while hypoxia protects cells from radiation (Oxygen enhancement ratio (OER)). Breast cancer stem cells (BSCSs) are protected from radiation by high levels of free radical scavengers even in the presence of oxygen. This led us to hypothesize that BCSCs exhibit an OER of 1. Using four established breast cancer cell lines (MCF-7, T47D, MDA-MB-231, SUM159PT) and primary breast cancer samples, we determined the number of BCSCs using cancer stem cell markers (ALDH1, low proteasome activity), compared radiation clonogenic survival and mammosphere formation under normoxic and hypoxic conditions, and correlated these results to the expression levels of key members of the free radical scavenging systems. The number of BCSCs increased with increased aggressiveness of the cancer. This correlated with increased radioresistance (SF8Gy), and decreasing OERs. When cultured as mammospheres, breast cancer cell lines and primary samples were highly radioresistant and not further protected by hypoxia (OER∼1).We conclude that because BCSCs are protected from radiation through high expression levels of free radical scavengers, hypoxia does not lead to additional radioprotection of BCSCs.
Highlights
In 1909 Gottwald Schwarz reported that a reduction in blood flow and oxygen supply protected the human skin from Xrays [1]
To assess the size of the breast CSCs (BCSCs) pool more directly we used two different marker systems: activity of ALDH1 and a system developed in our laboratory that uses lack of proteasome activity to identify BCSCs [13,14] and was recently shown to correlate with early recurrence in early stage breast cancer patients (T1/2, N0/1) after radiation therapy [15]
A recent meta-analysis studying 4805 patients with HNSCC treated in 32 randomized clinical trials reported improved loco-regional control (8%), disease-specific (7%) and overall survival (3%) if tumor hypoxia was modified [24]
Summary
In 1909 Gottwald Schwarz reported that a reduction in blood flow and oxygen supply protected the human skin from Xrays [1]. High intra-tumoral pressure and the irregular structure of the tumor blood vessels [2] hinders regular blood flow and primes the tumor vasculature to frequent occlusions by micro-thrombosis and subsequent recanalization, thereby causing changes between acute hypoxia and reoxygenation of those cancer cells that depend on the affected capillaries [3]. A general assumption is that during fractionated radiation treatment, normoxic cells are preferentially killed and portions of the surviving chronically hypoxic parts of the tumor are vascularized, oxygenated and sensitized to subsequent fractions of radiation [4]. Fractionated radiation normalizes the irregular structure of the vascular network inside of tumors, thereby reducing the frequency of micro-thrombosis and acute hypoxia [5]. Even though there is some controversy on which form of hypoxia is more important for treatment outcome, it is in general widely accepted that the hypoxic fraction of cells inside a tumor at the time of irradiation determines its curability
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