The functional role of HDL in the tumor microenvironment

Although massive scientific efforts have been and are currently undertaken to develop targeted therapies for the treatment of cancer, malignant neoplasms are still one of the global leading causes of death. In order to obtain a better understanding concerning the biology of cancerous tissues, the tumor microenvironment (TM) has become an attractive research target in the previous decade. By secreting pro- angiogenic factors such as VEGF, PDGF, and FGF, cancer cells activate adjacent host endothelial cells to enter an angiogenic program, which results in the formation of new blood vessel growth. Based on the assumption that blocking microvessel sprouting would sever tumor cells from access to nutrients or oxygen for growth and metastasis, high expectations were put into the development of antiangiogenic therapies. Whereas initial preclinical studies using inhibitors targeting the VEGF/VEGFR2 axis turned out as very promising, the success of clinical trials of angiogenesis inhibitors has been limited. Therefore, a more comprehensive understanding concerning intercellular communication in the TM is required to explore potential new targets that improve the results of current therapies. High-density lipoproteins (HDLs) represent the most heterogenous group of lipoproteins, with significant differences in protein and lipid content according to individual genetic and metabolic backgrounds. These lipoproteins are well known to mediate reverse cholesterol transport and to serve important cardioprotective/antiatherogenic functions. However, their role in cancer biology remains ambiguous, as recent studies described pro- and anti-tumorigenic/angiogenic properties of HDLs, pointing towards celltype- and cancer-specific functions. Whether the globally occurring metabolic changes during cancer initiation and progression influence HDL composition and function is not known. This research proposal will explore the interaction of HDL particles with cancer- and endothelial cells in the TM. Using breast, pancreas, and colon carcinoma cells and respective mouse tumor tissues we want to address the question whether these cellsissues express proteins that interact with HDL particles and/or influence their composition and function. We will compare the effects of HDLs from tumor bearing and control mice, as well as from cancer patients and healthy individuals on cancer- and endothelial cells, and determine their biochemical composition. Furthermore, the potential of cancer cells to synthesize angiogenesis-modulating HDL-like particles will be tested. Finally, we plan to investigate HDL-mediated effects in tumor growth and angiogenesis in vivo by using i) peritumoral injection studies of HDLs from heatlhy versus endstage tumor-bearing mice and ii) ApoA-I knockout mice, which show dramatical differences in HDL plasma levels and biochemical composition. By addressing these questions I would like to gain new insights into the role of HDL particles in the TM and the impact of cancer on the functionality of these lipoproteins. The overall research goal is to identify potential HDL-associated targets for the development of specific and efficient anti-cancer therapeutics.

In the last decades, obesity reached pandemic dimensions and is currently considered as one of the major health threats worldwide. Of note, clinical studies have clearly demonstrated that obesity and the metabolic syndrome are directly associated with the development and progression of cancer malignancies such as colorectal, ovarian, breast as well as pancreatic cancer. The decrease in blood concentrations of high-density lipoproteins (HDL), also well known as the good cholesterol, was identified as one potential clinical relevant factor that drives the progression of cancer in obese patients. This research project was dedicated to exploring the underlying mechanisms to explain the tumor-protective actions of HDL. Experiments with mouse models of pancreatic cancer revealed that HDL exerts an anti-tumor effect that is partially explained by the composition of the lipoprotein particle. HDL was able to decrease the tumor growth rate in mice and also blocked the expansion of pancreatic cancer cells in cell culture experiments. Importantly, this anti-tumor effect of HDL was not due to a decrease of the blood vessel supply of the tumor or the decreased infiltration of tumor-promoting immune cell populations. In contrast, HDL particles directly inhibited the growth of pancreatic cancer cells by binding to a cell surface receptor well known to regulate HDL-mediated cholesterol exchange at the cell membrane. The finding that HDL directly counteracts tumor progression has scientific but also socio- economic implications. From a scientific point, HDL was long thought to be one of the key therapeutic structures with the potential to oppose atherosclerosis by lowering cholesterol levels in the circulation. Various medical compounds that raise plasma HDL levels have been developed, but the high expectations remained largely unattained. The novel findings that HDL possesses anti-tumor activity might offer new opportunities to use those drugs in the context of tumor malignancies. Further basic and translational research approaches are needed to prove the clinical efficacy of HDL raising drugs in the cancer setting. Moreover, HDL levels are directly associated with metabolic health and a balanced diet. Therefore, creating public awareness for a healthy lifestyle that protects from metabolic as well as from cancerous disease is of central importance with a high socio-economic relevance given the worldwide fast expanding, pandemic dimensions of obesity and metabolic diseases.