Abstract
Hypoxia is associated with tumor radioresistance; therefore, a predictive marker for tumor hypoxia and a rational target to overcome it have been sought to realize personalized radiotherapy. Here, we show that serine protease inhibitor Kazal type I (SPINK1) meets these 2 criteria. SPINK1 expression was induced upon hypoxia (O2 < 0.1%) at the transcription initiation level in a HIF-dependent manner, causing an increase in secreted SPINK1 levels. SPINK1 proteins were detected both within and around hypoxic regions of xenografted and clinical tumor tissues, and their plasma levels increased in response to decreased oxygen supply to xenografts. Secreted SPINK1 proteins enhanced radioresistance of cancer cells even under normoxic conditions in EGFR-dependent and nuclear factor erythroid 2–related factor 2–dependent (Nrf2-dependent) manners and accelerated tumor growth after radiotherapy. An anti-SPINK1 neutralizing antibody exhibited a radiosensitizing effect. These results suggest that SPINK1 secreted from hypoxic cells protects the surrounding and relatively oxygenated cancer cells from radiation in a paracrine manner, justifying the use of SPINK1 as a target for radiosensitization and a plasma marker for predicting tumor hypoxia.
Highlights
Heterogeneity of tumor oxygenation, which results from imbalances between oxygen supply from the tumor vasculature and the oxygen demand of cancer cells and between the rate of vascular network development and that of cancer cell proliferation, is a characteristic feature of solid tumors [1, 2]
We successfully identified serine peptidase inhibitor Kazal type 1 (SPINK1) as a hypoxia-responsive secretory protein and revealed that its expression is induced at the transcriptional level in a HIF-dependent manner
We found that SPINK1 expression was induced at the transcription initiation level by hypoxic stimuli and treatment with PHD inhibitors or a proteasome inhibitor
Summary
Heterogeneity of tumor oxygenation, which results from imbalances between oxygen supply from the tumor vasculature and the oxygen demand of cancer cells and between the rate of vascular network development and that of cancer cell proliferation, is a characteristic feature of solid tumors [1, 2]. To overcome the hypoxia-induced radioresistance, many kinds of hypoxia-targeting strategies have been attempted [2], for example, delivery of molecular oxygen to hypoxic regions, combination with hypoxic cell radiosensitizers, and dose escalation to hypoxic tumor cells using intensity-modulated radiotherapy. Their effectiveness for local tumor control and/or overall survival is confirmed in a clinical setting as well as preclinical studies to varying degrees [2, 6, 8, 9]. None of these strategies has yet to be applied for clinical use with satisfactory results, which is, at least in part, attributed to limited understanding of the molecular pathways that determine hypoxic cell radioresistance
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