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Rudolph Virchow pioneered the hypothesis that inflammation exerts a profound influence on the development and biological behavior of cancer nearly 150 years ago, and since that time it has become increasingly apparent that microbial pathogens contribute to the genesis of a substantial number of malignancies worldwide . Conservative estimates indicate that nearly 15% of all cancer cases are attributable to infectious agents, translating to a malignant burden of 1.2 million cases per year . One mechanism that contributes to carcinogenesis induced by chronic pathogens is the concomitant inflammatory response that leads to the production of mutagenic substances, such as nitric oxide . Nitric oxide, in turn, can be converted to reactive nitrogen species, which nitrosylate a variety of cellular targets including DNA and proteins, and similarly, Superoxide anion radicals generated by polymorphonuclear cells induce DNA damage through the formation of DNA adducts. Viral agents can directly transform host cells by integrating active oncogenes into the host genome . Thus, there is precedence and support for the concept that infectious agents can initiate or promote pathways that eventuate in neoplasia.

Human T-cell lymphotropic virus type 1 (HTLV-1), is the causative agent of adult T-cell leukemia/lymphoma (ATLL) and a variety of immune-mediated disorders (Table 1). Currently, HTLV-1 infection occurs worldwide with endemic regions of higher prevalence. Natural transmission of these viruses occurs through cell-associated routes that include: orally from breast feeding, sexual contact, and by exposure to infected blood or whole cell blood products. While the molecular events of virus replication are beginning to be unraveled and knowledge about HTLV-1-associated diseases has increased, there remain many questions regarding the pathogenesis of the diseases associated with this complex retrovirus. In this chapter, we will focus on the pathogenesis and clinical presentation of ATLL with emphasis on new information regarding the viral etiology, pathologic lesions, patient susceptibility factors, host immune responses, and, in particular, the role of cytokines in the development of ATLL. The epidemiology and diseases associated with HTLV-1 are well known; however, the molecular mechanisms used by the virus to establish persistent infection and subsequently facilitate lymphocyte proliferation while circumventing immune elimination, remain less well defined.

Herpesviruses are large, enveloped, double-stranded DNA viruses, which are characterized by their ability to cause mild acute infections followed by lifelong latency in the host and periodic episodes of reactivation. The herpesviridae family is subdivided, based on their biologic properties, into the α-, β-, and γ-herpesvirinae and can be found in a wide variety of species (1).Of the eight human herpesviruses (HHV) identified to date, only two have been clearly shown to be oncogenic: Epstein-Barr virus (EBV, or HHV-4) and human herpesvirus 8 (HHV-8; also termed Kaposi’s sarcoma-associated herpesvirus, KSHV). Both viruses belong to the γ-herpesvirus subfamily, but are further subdivided as a lymphocryptovirus (EBV) or a rhadinovirus (HHV-8). They can infect cells of lymphoid origin, particularly B-cells, but also have a tropism for other cell types, such as epithelial cells for EBV and endothelial cells for HHV-8. Infection of susceptible cells with either of these herpesviruses results in the triggering of both a humoral and cellular immune response, which includes the expression of numerous cellular cytokines. Interestingly, in addition to inducing host cytokines, both EBV and HHV-8 encode homologues to cellular cytokines and their expression is important in both modulation of the host’s immune response to infection as well as viral-induced pathogenesis. In this chapter we will review cytokine responses, both virally encoded and cellular, that are produced as a result of EBV or HHV-8 infection focusing on those identified as having a potential role in carcinogenesis.

Tumor necrosis factor a (TNF) is a potent, pleiotropic, proinflammatory cytokine that is produced by macrophages, neutrophils, fibroblasts, keratinocytes, NK, T-and B-cells and also by tumor cells. TNF binds to either of two receptors, TNF-R1 or TNF-R2, expressed on virtually all mammalian cell types. TNF was named because of its ability, when administered in pharmacologic doses, to cause necrosis of tumors in experimental models. Recombinant TNF is approved in Europe to be given locoregionally as a therapy for sarcoma. TNF produced by the body mediates host responses in acute and chronic inflammatory conditions and aids in host protection from infection and malignancy. The biology of the TNF/TNF-receptor system was reviewed by .

Normal tissue homeostasis is maintained by strict regulation of interactions between cells and their microenvironment. How a cell responds to stimulatory and inhibitory signals it receives from the microenvironment will directly impact whether or not that particular cell will proceed through the cell cycle and proliferate or stop cell cycle progression and undergo assessment. When cells no longer respond to their microenvironmental cues and proliferate autonomously, tumors arise. The major known negative regulators of cell proliferation are the transforming growth factor βs (TGF-βs). The TGF-β signaling pathways are tumor suppressive, yet once tumors have developed, TGF-β signaling can enhance tumor progression.

The interleukin (IL)-l extended family (IL-lFx) of beta trefoil cytokines now includes a total of 11 members, many of which have been identified as being produced by dendritic cells (DC)s and acting on natural killer (NK) and T-cells. Their major role in immunity remains not fully explored but based on expression data and studies done over the last two decades it is expected that they are important for the initial critical events in NK cell/DC and T-cell/DC interactions, serving as cytokine danger signals or Signal Os alerting the host to damage or injury. They are likely important, following the delivery of antigen/MHC Signal 1 and B7/CD28 Signal 2s during polarization (Signal 3) of the immune response and during the effector phase, as potential Signal 4s associated with tissue specific signaling and homing, driving either inflammation or healing and the fibroblastic response, mediated by IL-Iβ during the effector phase of the immune response as Signal 5s . Alternatively they deliver activation signals across the immunologie synapse to T-cells and NK cells . A careful analysis of these factors and their role in NK cell/DC cross talk has not been performed, although analysis of these individual dendrikines in murine models and in vitro human studies suggest that at least IL-18 and a novel factor, IL-lF7b may play important antitumor roles. We will carefully extend observations with these IL-Is to other family members (IL-lFx), determine how they and their inhibitors regulate NK/DC interactions, and promote the adaptive immune response to tumor.

Both interleukin-4 (IL-4) and interleukin-13 (IL-13) are predominantly T-helper-2 (Th2) derived cytokines and share many structural and functional characteristics with each other. Both cytokines are also shown to be produced by mast cells and basophils . IL-4 was first identified in 1980s as a B-cell growth factor , and shown to mediate many effects on numerous cell types including T-cells, B-cells, monocytes, mast cells, endothelial cells, fibroblasts, astrocytes, and osteoblasts .

In 1956, Castleman et al. reported 13 patients who had localized mediastinal lymph node hyperplasia resembling thymoma . The characteristic features of the hyperplastic lymph nodes were follicular hyperplasia with a large germinal center penetrated by branching hyaline blood vessels and proliferation of hyaline capillaries with endothelial hyperplasia in the interfollicular areas. Thereafter, Flendrig et al. and Keller et al. independently reported another morphologic type of the benign giant lymph node characterized by hyperplastic germinal centers and intervening sheets of plasma cells . The former is referred to as the hyaline-vascular type (HV type) and the latter as the plasma cell type (PC type) of Castleman’s disease.

The Class II alpha helical family of cytokines now includes the extended Interleukin-10 family (IL-10, IL-19, IL-20, IL-22, and IL-26) as well as the closely related Interferon-a, Interferon-γ, and Interferon-τ . The importance of the distaff side of this family, the interferons , for cancer biology and tumor immunology has been well defined since the initial report of substances interfering with viral infection by Isaacs and Lindenmann almost 50 yr ago . Less clear, evolving, and more ambiguous has been the role of the IL-10 extended family defined in the last 15 yr, many of them with more interferon-like properties . In cancer patients with malignant melanoma , ovarian cancer , and other hematologic malignancies such as, lymphoma and multiple myeloma , IL-10 itself can be identified in the serum and/or tumor. Indeed, a negative correlation between circulating levels of IL-10 and prognosis has been reported. For this reason, IL-10 was suspected to be produced by tumor cells, followed by suppression of antitumor immune responses. IL-10 may also act as a tumor growth factor. For example, exogenous IL-10 administration causes expansion in a number of melanoma cell lines owing to the expression of IL-10 receptor . In contrast, IL-10 produced by some activated immune cells can promote antitumor activity and is indicative of a potent antitumor immune response. Thus, elevation of IL-10 levels does not always correlate with prognosis in patients with cancer, reflecting its complex biology.

Multiple myeloma (MM) is a clonal plasma cell neoplasm which remains incurable despite conventional therapy; and new treatment strategies are therefore urgently required . MM cells predominantly localize in bone marrow (BM), and their interaction with BM stromal cells (BMSCs) stimulates transcription and secretion of cytokines from BMSCs. Cytokines in turn not only promote the growth and survival of MM cells, but also reduce efficacy of conventional drugs . For example, adherence of MM cells to BMSCs triggers interleukin-6 (IL-6) and insulin-like growth factor-I (IGF-I), and vascular endothelial growth factor (VEGF) production from BMSCs, which induces MM cell growth and protect against dexamethasone (Dex)-induced MM apoptosis . High serum levels of IL-6 and IGF-I in MM patients also correlate with clinical drug-resistance in MM. Cytokines trigger three signaling cascades in MM cells: mitogen-activated extracellular kinase 2(MEK)/extracellular signal-regulated kinase (ERK); phosphatidylinositol-3 kinase (PI3-kinase)/AKT; and Janus kinases (JAK)-signal transducer and activator of transcription (STAT) pathways. Novel treatment strategies based on targeting these signaling pathways are now being designed to block cytokine-mediated growth/survival and drug-resistance. In this chapter, we review the role of various cytokines in the biology of MM, as well as novel therapies that overcome cytokine-mediated growth, survival, migration and chemoresistance.