Current Pharmaceutical Design - Volume 15, Issue 16, 2009

Inflammation and cancer are closely associated. Crosstalk between both disease processes starts at the level of carcinogenesis but is also implicated in tumor growth, progression and metastasis [1-4]. Although the inflammatory response can play a role in tumor suppression by stimulating an antitumor immune response, support of tumor development is more dominant. This makes a variety of anti-inflammatory pharmaceuticals interesting candidates for therapeutic intervention in cancer [5-8]. At the same time, it is not completely understood how cancer-associated inflammation is regulated and how pro- and anti inflammatory pathways can optimally be manipulated to maximize anticancer effects. Improving insight into the cells and mediators that play a role in the crosstalk between inflammation and cancer is the aim of this issue. In some cancer types, inflammation is present before a malignant change occurs. This so-called tumor-initiating inflammatory response can be caused by infectious agents, chronic irritation or chemical damage [9-11]. For example persistent bacterial infections, like Helicobacter pylori, predispose for gastric cancer, and Crohn's disease is associated with colon cancer. In addition, chronic inflammation caused by reflux esophagitis or asbestosis is clearly linked with esophageal adenocarcinoma and mesothelioma respectively. In many other types of cancer, however, inflammation is not the initiating trigger. Instead, oncogenic changes in these cancers frequently elicit an inflammatory tumor microenvironment that facilitates further tumor development and progression, i.e. cancer-associated inflammation [12]. For example, human breast cancer is frequently characterized by abundant presence of infiltrating immune cells, whereas breast cancer has not been directly linked with infectious conditions. Thus, also malignancies not directly linked to bacterial or viral infections are often associated with inflammation. Inflammation may develop into a chronic process when the cause for the inflammatory response is not eliminated or when the normal mechanisms that terminate the process fail. As a result, the balance between pro-and anti-inflammatory mediators is not restored and inflammation continues. It is believed that carcinogenesis is promoted by chronic inflammation as a result of local activation of stromal cells that release a variety of pro-inflammatory molecules that activate endothelium and attract circulatory inflammatory cells [13, 14]. The ensuing inflammatory reaction can promote tumor progression via direct and indirect mechanisms. For example, macrophages may be a source of reactive oxygen and nitrogen species which can cause direct damage to DNA by forming single or double-stranded breaks and stimulate recombination [15, 16]. Central enzyme in the damage by free radicals is cyclooxygenase 2 (COX-2) [17]. Consequently, drugs that inhibit this enzyme have been under investigation for their prophylactic activity. Apart from damage by reactive molecules, inflammatory cells also release cytokines that favor cell proliferation and survival, thereby increasing the number of cells that are at risk for mutations [18]. At the same time, angiogenic factors are released that stimulate new blood vessel growth [19, 20]. All in all, these pathways create a microenvironment that is susceptible to cancer development. It is important to recognize that the relation between proinflammatory stimuli and cancer is more subtle than suggested by the previous examples. There are also cases where infiltration of immune cells protects against cancer and examples of anti-inflammatory therapies that promote tumorigenesis [21, 22]. It is particularly the balance between anti and pro-inflammatory stimuli which needs to be repaired, requiring a pharmaceutical strategy that reflects this dual approach.

Inflammation is considered a hallmark of cancer. The chronic inflammatory process is driven by the interaction of cells, proteins, cytokines, transcription factors, and lipid mediators within the tumor microenvironment giving rise to complex pro-inflammatory cascades. These can be inhibited by a variety of different anti-inflammatory compounds, like non-steroidal anti-inflammatory drugs, glucocorticoids, anti-inflammatory biologicals, phytotherapeutics (mainly polyphenols), and drugs with pleiotropic anti-inflammatory effects. In general, it appears that the anti-tumor activity of these compounds occurs at higher doses than the doses used in conventional anti-inflammatory therapy. To optimally take advantage of the anti-tumor activity and at the same time limit side effects, targeted delivery of anti-inflammatory drugs appears an attractive approach.

Acquisition of resistance to the cytotoxic effects of anticancer agents is one of the most significant impediments to effective cancer therapy. Although various cancer-cell intrinsic mechanisms of drug resistance have been identified, chemotherapy resistance remains one of the major causes of cancer patient death. Emerging evidence suggests that the inflammatory tumor-microenvironment plays an important additional role in modulating drug responsiveness and drug resistance; however, underlying mechanisms are still largely unknown. In this review, we discuss data supporting the idea that crosstalk between components of the immune system and cancer cells can influence chemoresistance, and we will speculate on possible underlying pathways and clinical implications. A deeper understanding of the cancer cell-intrinsic and -extrinsic mechanisms of drug resistance will accelerate the development of novel combinatorial anticancer therapies in which drug resistance is prevented or reversed.

Vascular system plays critical roles in tumor progression and metastasis. Tumor vessels generally sprout from preexisting vascular cells. In addition, pluripotent progenitor cells also participate in tumor neovascularization. The latter populations include endothelial progenitor cells, hematopoietic stem cells and mesenchymal stem cells that are stimulated and attracted into the lesion. Recent studies on tumor microenvironment have disclosed that BM (bone marrow)-derived progenitor cells contain unique subpopulations that do not become fully-differentiated vascular constituents; instead, they show the nature of immature myeloid or mesenchymal lineage, and they enhance tumor angiogenic milieu in close contact with tumor vessels. BM-derived cells also migrate into pre-metastatic niche and stimulate vascular beds of distant organ for attracting circulating tumor cells. Currently, several antiangiogenic molecules are under clinical trials and they are expected to improve overall prognosis. Humanized monoclonal antibody bevacizumab specifically targeting VEGF (vascular endothelial growth factor), and several tyrosine kinase inhibitors targeting VEGF receptors-mediated pathways are the most widely studied agents in several types of advanced cancers. It is obvious that VEGF contributes to tumor neovascularization as a mastermind molecule. On the other hand, the mechanism has also been elucidated how tumors evade VEGF targeting therapies. To establish safer and more effective antiangiogenic therapies, it is important to understand the crosscommunication between tumors and hosts in proinflammatory milieu. In this review, we discuss features of tumor angiogenic vessels and their microenvironment. Recent topics on the contribution of BM-derived cells, complexities of VEGFtargeting approaches, and chemoattractants that activate tumor vascular beds are summarized.

A close interaction of cancer cells with their microenvironment is important for their growth and survival. In this respect, the involvement of inflammatory cells in the initiation, promotion and progression of cancer has pointed to new therapeutic opportunities in the treatment of cancer. The main immune cell types implicated in tumor-associated inflammation are macrophages, dendritic cells, lymphocytes, neutrophils, eosinophils and mast cells. Their precise role in intercellular communication, regulation of tumor inflammation, and to what respect this inflammation contributes to tumor development, are not completely understood. Mast cells are key effector cells in allergic diseases, but it has become apparent that they also contribute to other pathologies, including autoimmune diseases and cancer. Activated mast cells can release many pro-angiogenic and tumor growth stimulatory mediators. Increased numbers of mast cells are found in many tumors and it has been shown that the number of tumor infiltrating mast cells correlate with increased intratumoral microvessel density, enhanced tumor growth and tumor invasion, and poor clinical outcome. Therefore, modulating mast cell recruitment, viability, activity, or mediator release patterns at malignant sites can be of importance to control tumor growth. In this review, we will focus on the contribution of mast cells to tumor development and growth and the possibilities to interfere in mast cell activation and proliferation in the therapy of cancer.

Over the last years a number of reports have described elevated numbers of regulatory T (Treg) cells inside of tumors, in close proximity of the tumor, draining lymph nodes and also in peripheral blood of patients with solid tumors and hematologic malignancies. There is increasing evidence that Treg cells can migrate into tumors and suppress effective anti-tumor responses in the tumor microenvironment, thus contributing to the prosperity and growth of human tumors. In addition, several mechanisms have been described how conversion of conventional CD4+ T cells into Treg cells can occur in the context of human tumors, yet little is known about the molecular and cellular features responsible for the increase and maintenance of elevated levels of Treg cells in cancer. Recent studies now have elucidated how Treg cells mediate regulatory activity in the tumor microenvironment and enhanced our understanding of the underlying molecular mechanisms. Targeting Treg cells therefore provides an attractive therapeutic strategy to potentially influence the suppressed immune response in tumor patients thereby altering and supporting anti-tumor therapy.

Currently, the effect of AIDS single-target chemotherapy is severely compromised by the quick emergence of resistant HIV strains. Highly active antiretroviral therapy (HAART) combines HIV reverse transcriptase inhibitors with protease inhibitors or integrase inhibitors, and successfully suppresses HIV viral load to an undetectable level, dramatically improving the life quality of AIDS patients. However, the benefits of this approach are often compromised by poor patient compliance. Recently, there has been a move toward multicomponent drugs whereby two or more agents are coformulated in a single tablet to make dosing regimes simpler and thereby to improve patient compliance, but there are significant risks involved in the development of multicomponent drugs. Designed multiple ligands (DMLs) therapy as an emerging anti-HIV drug discovery paradigm, using a single entity to inhibit multitargets could yield improved patient compliance, thus reducing the likelihood of drug resistance. The exploration of such multifunctional ligands has proven valuable for anti-HIV leads discovery. However, presently many multifunctional scaffolds were first discovered by serendipity or screening; rational design by combining existing monofunctional scaffolds remains an enormous challenge. A key issue in the design of multiple ligands is attaining a balanced activity at each target of interest while simultaneously achieving a wider selectivity and a suitable pharmacokinetic profile. This review of literature examples introduce numerous attractive lead compounds, capable of interfering with different stages of HIV infection and AIDS pathogenesis, which reveals trends and insights that might provide valuable clues for novel anti-HIV drug design and help medicinal chemists discover the next generation of multiple ligands.

Advances in intensive care and antibiotics have prevented the spread of some infections, though sepsis mortality rates remain high. With failure of over thirty clinical trials, sepsis remains a scientific and clinical challenge in modern medicine. Sepsis is defined by the clinical signs of a systemic inflammatory response to infection. “Severe sepsis” is when these symptoms are associated with multiple organ dysfunction. These definitions of sepsis may be too broad and common to heterogeneous groups of patients who do not necessarily have the same disorder. This consideration has become especially evident in the clinical trials that have failed to obtain consistent results in similar studies of patients diagnosed with severe sepsis. In these trials, patients with infections caused by different microorganisms, and affecting different organs, have been combined under the general diagnosis of severe sepsis. The situation is analogous to attempting a clinical trial based on the general definition of cancer, combining all patients with tumor independent of the type of malignancy. In this consideration, it would not be very surprising that activated protein C, the only treatment in sepsis approved by the Food and Drug Administration, is projected for use in only a small subset of patients with severe sepsis. This article reviews novel inflammatory molecular aspects and the experimental anti-inflammatory strategies for sepsis, as they may represent particular pathological processes in specific subsets of patients.