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Targeted Inhibition of Cancer-Inflammation the Printing of This Thesis Was Financially Supported By Targeted inhibition of cancer-inflammation The printing of this thesis was financially supported by: Northern Lipids Inc. www.northernlipids.com ISBN: 978-90-393-5771-2 Dit werk is auteursrechtelijk beschermd. © 2012 M. Coimbra Printed by Ipskamp Drukkers B.V., Enschede, The Netherlands Cover design by Mikenzo Targeted inhibition of cancer-inflammation Doelgerichte remming van de ontstekingsrespons bij kanker (met een samenvatting in het Nederlands) Proefschrift ter verkrijging van de graad van doctor aan de Universiteit Utrecht op gezag van de rector magnificus, prof.dr. G.J. van der Zwaan, ingevolge het besluit van het college voor promoties in het openbaar te verdedigen op woensdag 25 april 2012 des middags te 2.30 uur door Maria José Gomes Coimbra geboren op 17 mei 1981 te Braga, Portugal Promotor: Prof. dr. G. Storm Co-promotor: Dr. R. M. Schiffelers This research is supported by the Dutch Technology Foundation STW, which is part of the Netherlands Organization for Scientific Research (NWO) and partly funded by the Ministry of Economic Affairs, Agriculture and Innovation (project number 07947). Para o meu pai Table of Contents Chapter 1 General introduction 9 Chapter 2 Targeted delivery of anti-inflammatory agents to tumors 25 Chapter 3 Liposomal glucocorticoids accumulate and inhibit tumor growth in a spontaneous mouse mammary tumor model 75 Chapter 4 Anti-tumor efficacy of dexamethasone-loaded core-crosslinked polymeric micelles 93 Chapter 5 Liposomal pravastatin inhibits tumor growth by targeting cancer- related inflammation 113 Chapter 6 Improving solubility and chemical stability of natural compounds for medicinal use by incorporation into liposomes 135 Chapter 7 Critical factors in the development of tumor-targeted anti- inflammatory nanomedicines 161 Chapter 8 Summarizing discussion 179 Chapter 9 Appendix 187 7 8 Chapter General introduction 1 Maria Coimbra Inflammation – calor, dolor, rubor, tumor and functio laesa An inflammatory response is a dynamic and complex defense mechanism of the host to tissue injury or, more in general, loss of cell or tissue homeostasis. A multifactorial network of mediators and cellular effectors initiate and promote elimination of invading pathogens, 1 tissue remodeling and/or repair [1]. Primarily the inflammatory response involves a non- specific line of defense with activation and migration of cells of the innate immune system to the afflicted tissue [1]. Tissue-resident monocytes (that differentiate into macrophages at the damaged site) and mast cells release various chemokines, cytokines and growth factors designed to interfere with endothelial, epithelial and mesenchymal cell- function [1]. Overall this leads to a number of macroscopic changes in the tissue: increase in blood flow and redness (rubor), local increase in temperature (calor), vasodilation and exsudation (edema, tumor), stimulation of sensory nerves (dolor) and loss of function (functio laesa) [2]. Chemotactic cytokines orchestrate the recruitment of additional leukocyte subpopulations from the circulation, especially neutrophils and macrophages. Activated and adherent leukocytes roll over the vascular endothelium and extravasate into the damaged tissue to engulf the foreign material and cell debris. Subsequently, the venous network is restored and tissue remodeling and repair takes place by proliferating endothelial cells and fibroblasts within the extracellular matrix of the damaged tissue. After the pathogenic trigger is removed, infiltrating cells undergo apoptosis or exit the tissue via lymphatic drainage and the assortment of signaling molecules shifts from pro- inflammatory to anti-inflammatory with resolution of inflammation [3]. The inflammatory response sketched above is usually a self-limiting process, however persistence of the initiating factors or a failure to resolve the inflammatory response can lead to pathogenesis [3]. Cancers – wounds that fail to heal Such persistent inflammation is now considered to be a hallmark of cancer. Since the observation by Virchow in 1863 that neoplastic lesions are infiltrated by inflammatory cells, the link between chronic inflammation and cancer has strengthened particularly in the last decade [4]. The strongest correlations between chronic inflammation and development of malignancy are: colon carcinogenesis in individuals with inflammatory bowel disease, hepatocellular carcinoma in individuals with chronic hepatitis virus infection, and gastric cancer following Helicobacter pylori infection [4-6]. “Smoldering” 10 inflammation is nowadays recognized as supportive for tumor initiation, promotion and progression rather than a protective mechanism to raise an effective host anti-tumor response (Figure 1) [7-8]. Repeated tissue damage/repair with the persistence of an inflammatory cell infiltrate may lead to genomic alterations such as point mutations, 1 General introduction General Figure 1. Cancer-related inflammation. Tumor-promoting inflammation and antitumor immunity coexist at the different stages of tumorigenesis. Inflammation may contribute to tumor initiation, process in which normal cells acquire a first mutational hit, through mutations, genomic instability, and epigenetic modifications (mutated cells are marked with “x”). The activation of wound healing processes leads to increased proliferation and survival of the premalignant cells into a fully developed primary tumor, i.e., tumor promotion. Tumor cells and tumor- infiltrating immune/inflammatory cells produce signaling mediators that induce angiogenesis, immune evasion, growth and eventually metastatic spread. In yellow, stromal cells; brown, malignant cells; red, blood vessels; blue, immune and inflammatory cells. EMT, epithelial- mesenchymal transition; ROS, reactive oxygen species; RNI, reactive nitrogen intermediates. Adapted with permission from [8] 11 deletions, or rearrangements [9-10]. The inactivation of tumor suppressor genes, such as p53, is present in many tumors and determines their extended cell proliferation and life span, together with a deficient response to DNA damage in inflamed tissue [4, 10]. Irreversible changes of the DNA of proliferating cells may also be induced by reactive 1 oxygen (ROS) and nitrogen (RNS) species produced by many phagocytic cells while fighting chemical and viral carcinogens - these processes altogether form the initiation [9-10]. Until a second alteration takes place - promotion, these initiated cells or “subthreshold neoplastic states” can persist indefinitely [9]. Promoters include factors released at the site of damage, chronic inflammation and irritation, which generally induce cell proliferation, recruitment of inflammatory cells, continued production of ROS and NOS with further DNA damage and limited repair [9]. Healthy cells engage in these initiation and promotion stages, acquiring new mutations and deregulations that translate in insensitivity to anti-growth signals, resistance to apoptosis, self-sufficiency to proliferate, limitless replicative potential - tumor progression [8-9]. Furthermore, at a certain point, all solid malignancies outpace their blood supply becoming hypoxic and deprived of nutrients [11]. The necrotic cell death, especially at the tumor’s core, promotes the release of pro-inflammatory mediators that further induce neoangiogenesis and lymphoangiogenesis and ensure survival of cancer cells - the “angiogenic switch” [11]. Cytokines, chemokines and growth factors produced by both malignant and inflammatory cells drive the polarization of the tumor microenvironment, subverting adaptive immune responses, fostering proliferation, survival and migration [12-13]. For this reason, tumors act as wounds that fail to heal [14]. On closer examination, tumors contain a variety of cell types. Tumors should, therefore, be considered as an organ composed of not only tumor cells, but also innate immune cells (neutrophils, dendritic cells, macrophages, natural killer cells and mast cells), adaptive immune cells (B and T lymphocytes) and surrounding stroma (consisting of endothelial cells, fibroblasts, mesenchymal cells and pericytes) in a complex crosstalk and architecture [7-8, 12]. Even cancers not causally related to a pre-existing infection or inflammation can display massive inflammatory cell infiltrate due to the direct or indirect capability of oncogenes to induce production of inflammatory mediators and recruitment of inflammatory cells [5, 8]. Activated cells of the adaptive immune system, in a similar manner as during an inflammatory response, are capable of continuously recognize (immunosurveillance) and eliminate nascent tumors (immuno-editing) due to 12 the expression of “non-self” antigens by tumor cells [8, 15-16]. However, new cancer cell variants may evade the immunosurveillance due to their genetic instability [5, 8, 15]. Intriguingly, it seems that tumor-promoting inflammation and immunoediting can coexist at different points along the different stages of tumorigenesis [5, 8]. Besides having anti- tumor efficacy, immune cells also have tumor promoting effects, as they are reprogrammed 1 by the tumor cells towards an immunosuppressive and pro-angiogenic phenotype [13, introduction General 17-18]. For example, dendritic cells that are infiltrating tumors are usually immature and not able to effectively raise a T-cell anti-tumor response [19-21]. Tumor-associated macrophages (TAM) are the focus of attention of many research groups due to their dual role in carcinogenesis and major contribution to myeloid cell infiltrate in tumors.
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