PNNL

Abstract

Therapeutic hyperthermia involves raising the temperature of a tumor tissue to 40–43°C. It has been used for treatment of ovarian and other cancers. The rationale for this therapy is based on the direct-killing effects of temperatures above 41-42°C (Wust et al., 2002). Hyperthermia is also applied as an adjunctive therapy with various established cancer treatments, such as radiotherapy and chemotherapy, to sensitize cancers to their effects (Moyer and Delman, 2008; Nagata et al., 1997; Palazzi et al., 2010). Some studies suggested that hyperthermia activates the immune systems against tumor cells by increasing the release of heat shock proteins (HSPs) associated with tumor-specific antigens from heat-stressed or dying tumor cells that are phagocytized by antigen-presenting cells (APCs) (Binder et al., 2000). As interest in hyperthermic treatment of cancer has increased, researchers have made significant progress in developing strategies to heat tumors via local, regional, and whole-body hyperthermia with advancements in surgical techniques, equipment, and nanotechnology (van der Zee, 2002). In localized hyperthermia, heat is applied to a small area restricted to the tumor using various techniques that deliver energy for heating. Different types of energy may be used, including microwaves and radio waves (Gazelle et al., 2000; Seki et al., 1999), magnetic heating (Lee et al., 2011; Rodriguez-Luccioni et al., 2011), and ultrasound (Jolesz and Hynynen, 2002). Regional hyperthermia is applied via perfusion of a limb, organ, or body cavity with heated fluids. For example, the intraperitoneal route of heated chemotherapy administration (hyperthermic intraperitoneal chemotherapy [HIPEC]), which usually lasts 60-120 min with continuous cycling of the chemotherapeutic agent at 42°C, enables direct contact between the tumor cells and the chemotherapeutic agent to control all residual microscopic disease, including microscopic ovarian cancers (Jinny Ha, 2012). Even though hyperthermia is a promising improvement of cancer treatment, multiple obstacles remain to be cleared. One of the major issues is that the tumor temperatures that must be reached for obtaining clinical efficacy are undefined (Wust et al., 2002). In the present study, we monitored the temperature transition in tumors during HIPEC in ovarian cancer patients (Figure S1). Even though the perfusion temperature at the entrance was maintained at 42.5°C, the temperature in most of the tumors was about 40°C, which is the temperature seen with just a high fever, and the clinical benefit of these lower temperatures was unclear. Also, no data on predictors of sensitivity of ovarian and uterine tumors to hyperthermia has been addressed. The purpose of the present study was to determine the molecular mechanism of response of gynecological cancer cells to hyperthermia. We hypothesized that inhibition of a critical gene of hyperthermia resistance by small interfering RNA (siRNA) can sensitize ovarian and uterine cancers to hyperthermia. To achieve this, we explored the genes that regulate hyperthermia resistance by comparing gene and protein expression between hyperthermia sensitive and resistant cells. We performed that silencing of the novel target gene could sensitize hyperthermia resistant cancer cells to hyperthermic treatment both in vitro and orthotopic ovarian cancer models in vivo with copper sulfate nanoparticles and near-infrared laser treatment.