| Project Detail |
All Disciplines (2)
Discipline
Physiology : other topics
Experimental Cancer Research
Keywords (4)
hypoxia, high altitude, tumor, cancer
Lay Summary (German)
Lead
Title of the research project: Cancer Mortality: The Role of Hypoxia / High Altitude, Erythropoietin (Epo), Iron and Exercise Cancer Mortality: The Influence of Hypoxia and Height Exposure, Erythropoietin, Iron and Physical Movement The blood-forming hormone erythropoietin (Epo) Treatment of tumor-associated anemia (low blood glucose). Unfortunately, some tumor cells respond to Epo administration with increased growth. In addition, cancer affects the iron budget. In other words, the treatment of tumor anemia, which adversely affects the course of the disease, is a two-sided sword - usually necessary but with risks. On the other hand, the elevation reduces the occurrence of anemia and the need for Epo to normalize the blood levels.
Lay summary
Content and Objectives:
Our project is made up of 3 parts: (i) We study the effects of epo and iron in mice that spontaneously develop tumors and tumor-associated anemia. II) We analyze how the altitude can correct tumor-related anaemias and whether physical movement enhances this effect. In addition, we also investigate the direct influence on the level of tumor aggressiveness and metastasis. III) We work out how the effectiveness of cancer drugs changes in height. In the case of the chemotherapeutic drug Taxol, for example, we investigate changes in the breakdown or detoxification as well as distribution in the body or in the tumor.
Scientific and social context: The
aim of our project is to gain new insights into the correlation between high-altitude exposures (hypoxia) and tumor anemia, tumormalignment and therapeutic interventions. These findings are initially located in the area of ??basic research, but are intended to provide guidance for future therapeutic interventions in cancer therapy.
Direct link to Lay Summary Last update: 03.10.2017
Responsible applicant and co-applicants
Name Institute
Gassmann Max Institute of Veterinary Physiology Vetsuisse Faculty University of Zurich
Associated projects
Number Title Start Funding scheme
156481 Reduced incidence of cancer at high altitude: analyzing the impact of hypoxia on tumor development 01.10.2014 Project support (Dept. I-III)
Abstract
Anemia of cancer is a frequently occurring comorbidity in cancer patients promoting malignancy and compromising therapeutic interventions and is, as such, a poor prognosis factor for patient survival. Anemia is typically treated with erythropoietin (Epo) but reduced iron levels may render this medication ineffective. Consequently, iron supplementation alone or in combination with Epo is frequently used in cancer patients with iron deficiency to stimulate red blood cell formation. However, some cancer cells express the Epo receptor implying that Epo treatment may enhance tumor growth. Furthermore, high iron levels in humans are associated with increased cancer risk and disturbed iron homeostasis in cancer cells contributes to tumor malignancy. In other words, Epo and iron treatment is a double-edged sword: Both are essential to treat anemia of cancer but might increase the risk to enhance malignancy of a given cancer. Exposure to high altitude (HA) is associated with reduced incidence of anemia in patients with renal disease. Additionally, these patients require less often as well as lower dosages of Epo to treat anemia and display better survival rates. HA is a physiological challenging environment that demands humans to adapt to hypoxia. Maladaptation often leads to the development of HA-related diseases like acute or chronic mountain sickness. However, highlanders, i.e. humans constantly living at elevated areas, show reduced cancer mortality. The mechanisms that result in reduced cancer mortality are unknown but reduced anemia of cancer, as well as alteration in tumor perfusion, metastasis and efficacy of drugs, may account for it. Our proposal consists of 3 subprojects: First, we will treat our unique and recently established iron-deficient and anemia of cancer developing mouse model (Trp53floxWapCre) with iron and Epo to analyze: i) if iron supplementation alone or in combination with Epo ameliorates anemia and ii) if iron and/or Epo negatively impact on the tumor and promote its progression. Our project involves a novel anemia of cancer mouse model that will be treated with both, iron and Epo to explore the impact of iron and Epo as therapeutics for AC on tumor progression. Secondly, we aim to unravel how exposure to HA and hypoxia impacts on anemia of cancer and, based on our preliminary results, how physical activity (i.e. exercise) further stimulates erythropoiesis. Additionally, we will analyze how exposure to HA changes tumor vascularization (and thereby perfusion and oxygen transport) and tumor hypoxia. Finally, dissemination and colonization of tumor cells in distant tissues will be explored in hypoxia or HA-exposed animals, since metastasis often has a higher relevance in cancer patient survival that the growth of the primary tumor. In the third subproject, we will analyze the efficacy as well as pharmacokinetics and /dynamics of Taxol (Paclitaxel) in tumor-bearing and tumor free animals. Exposure to HA hardly affects the growth of the primary tumors in our models tested. However, preliminary data suggest that Taxol delays tumor growth more efficient in mice exposed to HA. Consequently, we will particularly analyze the distribution and metabolism of Taxol in HA-exposed mice as well as the underlying mechanisms (e.g. increased ROS formation) that may account for such improved treatment responses. In conclusion, we propose a comprehensive project that will help to understand the relationship between cancer, anemia of cancer and HA or hypoxia, respectively. We have designed our experiments to cover and to address a broad spectrum of oxygen-related open or insufficiently answered research questions in cancer. |
