Macrophage chemoattractants secreted by cancer cells: Sculptors of the tumor microenvironment and another crucial piece of the cancer secretome as a therapeutic target

Beyond their essential role in leukocyte homing in the context of inflammation, chemokines orchestrate the host response to cancer progression. Chemokines are key accelerators in the amplification of inflammatory signals and metastasis in the distal zone of tumors, indicating possible immune editing of tumor cells in the microenvironment. This review summarizes the main macrophage-attracting chemokines secreted from cancer cells and how these mediators can be targeted to improve cancer immunotherapy in multiple cancer types.     

The expression and role of CXC chemokines in colorectal cancer

Cancer is a life-threatening disease world-wide and colorectal cancer is the second common cause of cancer mortality. The interaction between tumor cells and stromal cells plays a crucial role in tumor initiation and progression and is partially mediated by chemokines. Chemokines predominantly participate in the chemoattraction of leukocytes to inflammatory sites. Nowadays, it is clear that CXC chemokines and their receptors (CXCR) may also modulate tumor behavior by several important mechanisms: regulation of angiogenesis, activation of a tumor-specific immune response by attracting leukocytes, stimulation of tumor cell proliferation and metastasis. Here, we review the expression and complex roles of CXC chemokines (CXCL1 to CXCL16) and their receptors (CXCR1 to CXCR6) in colorectal cancer. Overall, increased expression levels of CXC chemokines correlate with poor prognosis.     

浸润性中性粒细胞在促进肿瘤进展中的作用

中性粒细胞是机体外周血中数量最多的白细胞,在人体非特异性免疫系统中发挥着十分重要的作用.早期的研究认为,中性粒细胞能通过分泌细胞因子和产生活性氧等物质杀伤肿瘤.然而随着研究的深入,发现肿瘤微环境中的中性粒细胞对肿瘤的发展起到促进的作用.浸润性中性粒细胞产生的细胞因子和趋化因子能影响肿瘤微环境中炎症细胞的招募和激活,为肿瘤的发展提供良好的免疫抑制微环境,调控肿瘤的生长、转移和血管生成,还在肿瘤患者预后评估方面发挥着重要的作用.     

TLR4 signaling in cancer cells promotes chemoattraction of immature dendritic cells via autocrine CCL20

Toll-like receptors (TLRs) are involved in the production of inflammatory mediators upon specific ligands stimuli. Chemokines are important inflammatory mediators capable of chemoattracting diverse immune cells. In addition to normal immune cells, the expression of TLRs and chemokines has been detected in various tumor cells. However, the roles of TLRs and chemokines expressed by tumor cells in the processes of tumor progression and immune escape have not been fully elucidated. Here we report that TLR4 ligation by lipopolysaccharide (LPS) significantly promotes CT-26 colon cancer cells to produce chemokine CCL20 via activation of TLR4 signaling pathways. We find that LPS treatment of CT-26 cells can significantly increase the chemoattraction of immature dendritic cells (DC) by the autocrine CCL20. Our studies suggest that TLR4 expressed by tumor cells may be involved in the induction of chemokines like CCL20, providing a potential linkage between chronic inflammation and tumor immune escape.     

CCR2 expression correlates with prostate cancer progression

Although the primary role of chemokines and their receptors is controlling the trafficking of leukocytes during inflammatory responses, they also play pleoitropic roles in cancer development. There is emerging evidence that cancer cells produce chemokines that induce tumor cell proliferation or chemotaxis in various cancer types. We have previously reported that MCP-1 acts as a paracrine and autocrine factor for prostate cancer (PCa) growth and invasion. As the cellular effects of MCP-1 are mediated by CC chemokine receptor 2 (CCR2), we hypothesized that CCR2 may contribute PCa progression. Accordingly, we first determined CCR2 mRNA and protein expression in various cancer cell lines, including PCa and other cancer types. All cells expressed CCR2 mRNA and protein, but in PCa, more aggressive cancer cells such as C4-2B, DU145, and PC3 expressed a higher amount of CCR2 compared with the less aggressive cancer cells such as LNCaP or non-neoplastic PrEC and RWPE-1 cells. Further, we found a positive correlation between CCR2 expression and PCa progression by analyzing an ONCOMINE gene array database. We confirmed that CCR2 mRNA was highly expressed in PCa metastatic tissues compared with the localized PCa or benign prostate tissues by real-time RT-PCR. Finally, CCR2 protein expression was examined by immunohistochemical staining on tissue microarray specimens from 96 PCa patients and 31 benign tissue controls. We found that CCR2 expression correlated with Gleason score and clinical pathologic stages, whereas lower levels of CCR2 were expressed in normal prostate tissues. These results suggest that CCR2 may contribute to PCa development.     

Characterization of chemokines and their receptors in the central nervous system: physiopathological implications

Chemokines represent key factors in the outburst of the immune response, by activating and directing the leukocyte traffic, both in lymphopoiesis and in immune surveillance. Neurobiologists took little interest in chemokines for many years, until their link to acquired immune deficiency syndrome-associated dementia became established, and thus their importance in this field has been neglected. Nevertheless, the body of data on their expression and role in the CNS has grown in the past few years, along with a new vision of brain as an immunologically competent and active organ. A large number of chemokines and chemokine receptors are expressed in neurons, astrocytes, microglia and oligodendrocytes, either constitutively or induced by inflammatory mediators. They are involved in many neuropathological processes in which an inflammatory state persists, as well as in brain tumor progression and metastasis. Moreover, there is evidence for a crucial role of CNS chemokines under physiological conditions, similar to well known functions in the immune system, such as proliferation and developmental patterning, but also peculiar to the CNS, such as regulation of neural transmission, plasticity and survival.     

CXCR4/CXCL12 在肿瘤中的研究进展

研究表明趋化因子及其受体在胚胎发育、干细胞迁移以及各种免疫反应中发挥重要作用,是许多生理及病理过程中细胞运动的重要因素。趋化因子受体CXCR4是一个由352个氨基酸构成的、7次跨膜的G蛋白偶联受体。趋化因子CXCL12为其特异性受体。研究发现,CXCR4/CXCL12在多种肿瘤中都有表达,在肿瘤的生长、血管生成、转移等方面发挥着重要作用。与正常组织相比,肿瘤组织及转移灶CXCR4高表达。因此,对CXCR4/CXCL12轴在肿瘤病生理中的作用机制进行进一步研究,很可能为肿瘤的治疗及对肿瘤转移的预防提供一个新的思路。我们现在就对其在肿瘤病生理中的作用做一综述。     

Chemokines and chemokine receptors in leukocyte trafficking

Chemokines regulate inflammation, leukocyte trafficking, and immune cell differentiation. The role of chemokines in homing of naive T lymphocytes to secondary lymphatic organs is probably the best understood of these processes, and information on chemokines in inflammation, asthma, and neurological diseases is rapidly increasing. Over the past 15 years, understanding of the size and functional complexity of the chemokine family of peptide chemoattractants has grown substantially. In this review, we first present information regarding the structure, expression, and signaling properties of chemokines and their receptors. The second part is a systems physiology-based overview of the roles that chemokines play in tissue-specific homing of lymphocyte subsets and in trafficking of inflammatory cells. This review draws on recent experimental findings as well as current models proposed by experts in the chemokine field.     

Chemokines and autoimmune thyroid diseases.

Chemokines are a family of small, structurally related molecules that regulate cell trafficking of various types of leukocytes through interactions with their seven-transmembrane, G protein-coupled receptors. Their major function is the recruitment of leukocytes to inflammation sites, but they also play roles in tumor growth, angiogenesis, organ sclerosis, and autoimmunity. A variety of evidence has accumulated to support the concept that thyroid follicular cells as well as intrathyroidal lymphocytes are able to produce CC and CXC chemokines, which, in turn, promote the initiation and maintenance of an inflammatory process resulting in autoimmune thyroid diseases (AITD). Overexpression of several chemokines in AITD has been demonstrated. Moreover, alterations of CCL2, CCL5, CXCL9, and CXCL10 have been shown in circulation of many patients with AITD. In subjects with Graves' disease, antithyroid drug treatment, radioactive iodine ablation, and thyroidectomy can significantly reduce CXCL10 levels. The measurement of chemokines in serum of AITD patients might provide a useful parameter for the evaluation and prediction of disease activity and progression. Further experimental and clinical studies will expand our understanding of the clinical implications of chemokine detection and the effects of chemokines on the pathogenesis of AITD.     

The role of CXC chemokines in the transition of chronic inflammation to esophageal and gastric cancer

Chronic inflammation may increase the risk to develop cancer, for instance esophagitis or gastritis may lead to development of esophageal or gastric cancer, respectively. The key molecules attracting leukocytes to local inflammatory sites are chemokines. We here provide a systematic review on the impact of CXC chemokines (binding the receptors CXCR1, CXCR2, CXCR3 and CXCR4) on the transition of chronic inflammation in the upper gastrointestinal tract to neoplasia. CXCR2 ligands, including GRO-α,β,γ/CXCL1,2,3, ENA-78/CXCL5 and IL-8/CXCL8 chemoattract pro-tumoral neutrophils. In addition, angiogenic CXCR2 ligands stimulate the formation of new blood vessels, facilitating tumor progression. The CXCR4 ligand SDF-1/CXCL12 also promotes tumor development by stimulating angiogenesis and by favoring metastasis of CXCR4-positive tumor cells to distant organs producing SDF-1/CXCL12. Furthermore, these angiogenic chemokines also directly enhance tumor cell survival and proliferation. In contrast, the CXCR3 ligands Mig/CXCL9, IP-10/CXCL10 and I-TAC/CXCL11 are angiostatic and attract anti-tumoral T lymphocytes and may therefore mediate tumor growth retardation and regression. Thus, chemokines exert diverging, sometimes dual roles in tumor biology as described for esophageal and gastric cancer. Therefore extensive research is needed to completely unravel the complex chemokine code in specific cancers. Possibly, chemokine-targeted cancer therapy will have to be adapted to the individual's chemokine profile.     

The role of CXC chemokines in the transition of chronic inflammation to esophageal and gastric cancer

Chronic inflammation may increase the risk to develop cancer, for instance esophagitis or gastritis may lead to development of esophageal or gastric cancer, respectively. The key molecules attracting leukocytes to local inflammatory sites are chemokines. We here provide a systematic review on the impact of CXC chemokines (binding the receptors CXCR1, CXCR2, CXCR3 and CXCR4) on the transition of chronic inflammation in the upper gastrointestinal tract to neoplasia. CXCR2 ligands, including GRO-α,β,γ/CXCL1,2,3, ENA-78/CXCL5 and IL-8/CXCL8 chemoattract pro-tumoral neutrophils. In addition, angiogenic CXCR2 ligands stimulate the formation of new blood vessels, facilitating tumor progression. The CXCR4 ligand SDF-1/CXCL12 also promotes tumor development by stimulating angiogenesis and by favoring metastasis of CXCR4-positive tumor cells to distant organs producing SDF-1/CXCL12. Furthermore, these angiogenic chemokines also directly enhance tumor cell survival and proliferation. In contrast, the CXCR3 ligands Mig/CXCL9, IP-10/CXCL10 and I-TAC/CXCL11 are angiostatic and attract anti-tumoral T lymphocytes and may therefore mediate tumor growth retardation and regression. Thus, chemokines exert diverging, sometimes dual roles in tumor biology as described for esophageal and gastric cancer. Therefore extensive research is needed to completely unravel the complex chemokine code in specific cancers. Possibly, chemokine-targeted cancer therapy will have to be adapted to the individual's chemokine profile.     

Dual roles of immune cells and their factors in cancer development and progression

Traditional wisdom holds that intact immune responses, such as immune surveillance or immunoediting, are required for preventing and inhibiting tumor development; but recent evidence has also indicated that unresolved immune responses, such as chronic inflammation, can promote the growth and progression of cancer. Within the immune system, cytotoxic CD8(+) and CD4(+) Th1 T cells, along with their characteristically produced cytokine IFN-γ, function as the major anti-tumor immune effector cells, whereas tumor associated macrophages (TAM) or myeloid-derived suppressive cells (MDSC) and their derived cytokines IL-6, TNF, IL-1β and IL-23 are generally recognized as dominant tumor-promoting forces. However, the roles played by Th17 cells, CD4(+) CD25(+) Foxp3(+) regulatory T lymphocytes and immunoregulatory cytokines such as TGF-β in tumor development and survival remain elusive. These immune cells and the cellular factors produced from them, including both immunosuppressive and inflammatory cytokines, play dual roles in promoting or discouraging cancer development, and their ultimate role in cancer progression may rely heavily on the tumor microenvironment and the events leading to initial propagation of carcinogenesis.     

The Chemokine CXCL16 and Its Receptor,CXCR6, as Markers and Promoters of Inflammation-Associated Cancers

Clinical observations and mouse models have suggested that inflammation can be pro-tumorigenic. Since chemokines are critical in leukocyte trafficking, we hypothesized that chemokines play essential roles in inflammation-associated cancers. Screening for 37 chemokines in prostate cancer cell lines and xenografts revealed CXCL16, the ligand for the receptor CXCR6, as the most consistently expressed chemokine. Immunohistochemistry and/or immunofluorescence and confocal imaging of 121 human prostate specimens showed that CXCL16 and CXCR6 were co-expressed, both on prostate cancer cells and adjacent T cells. Expression levels of CXCL16 and CXCR6 on cancer cells correlated with poor prognostic features including high-stage and high-grade, and expression also correlated with post-inflammatory changes in the cancer stroma as revealed by loss of alpha-smooth muscle actin. Moreover, CXCL16 enhanced the growth of CXCR6-expressing cancer and primary CD4 T cells. We studied expression of CXCL16 in an additional 461 specimens covering 12 tumor types, and found that CXCL16 was expressed in multiple human cancers associated with inflammation. Our study is the first to describe the expression of CXCL16/CXCR6 on both cancer cells and adjacent T cells in humans, and to demonstrate correlations between CXCL16 and CXCR6 vs. poor both prognostic features and reactive changes in cancer stoma. Taken together, our data suggest that CXCL16 and CXCR6 may mark cancers arising in an inflammatory milieu and mediate pro-tumorigenic effects of inflammation through direct effects on cancer cell growth and by inducing the migration and proliferation of tumor-associated leukocytes.     

Inflammation in EAE: Role of chemokine/cytokine expression by resident and infiltrating cells

Experimental allergic encephalomyelitis (EAE) is an inflammatory demyelinating disease of the central nervous system (CNS) which has many clinical and pathological features in common with multiple sclerosis (MS). Comparison of the histopathology of EAE and MS reveals a close similarity suggesting that these two diseases share common pathogenetic mechanisms. Immunologic processes are widely accepted to contribute to the initiation and continuation of the diseases and recent studies have indicated that microglia, astrocytes and the infiltrating immune cells have separate roles in the pathogenesis of the MS lesion (1,2). The role of cytokines as important regulatory elements in these immune processes has been well established in EAE and the presence of cytokines in cells at the edge of MS lesions has also been observed (3–7). However, the role of chemokines in the initial inflammatory process as well as in the unique demyelinating event associated with MS and EAE has only recently been examined. A few studies have detected the transient presence of selected chemokines at the earliest sign of leukocyte infiltration of CNS tissue and have suggested astrocytes as their cellular source (8–10). Based on these studies, chemokines have been postulated as a promising target for future therapy of CNS inflammation. This review summarizes the events that occur during the inflammatory process in EAE and discusses the roles of cytokine and chemokine expression by the resident and infiltrating cells participating in the process. Special issue dedicated to Dr. Marion E. Smith.     

Deficiency of P-selectin or P-selectin glycoprotein ligand-1 leads to accelerated development of glomerulonephritis and increased expression of CC chemokine ligand 2 in lupus-prone mice

The selectins and their ligands mediate leukocyte rolling on endothelial cells, the initial step in the emigration cascade leading to leukocyte infiltration of tissue. These adhesion molecules have been shown to be key promoters of acute leukocyte emigration events; however, their roles in the development of long-term inflammatory responses, including those that occur during chronic inflammatory diseases such as systemic lupus erythematosus, are unclear. To assess participation of P-selectin in such disorders, we studied the progression of systemic lupus erythematosus-like disease in P-selectin-deficient and control MRL/MpJ-Fas(lpr) (Fas(lpr)) mice. Surprisingly, we found that P-selectin deficiency resulted in significantly earlier mortality, characterized by a more rapid development of glomerulonephritis and dermatitis. Expression of CCL2 (MCP-1) was increased in the kidneys of P-selectin mutant mice and in supernatants of LPS-stimulated primary renal endothelial cell cultures from these mice. A closely similar phenotype, including elevated renal expression of CCL2, was also observed in Fas(lpr) mice deficient in the major P-selectin ligand, P-selectin glycoprotein ligand-1. These results indicate that P-selectin and P-selectin glycoprotein ligand-1 are not required for leukocyte infiltration and the development of autoimmune disease in Fas(lpr) mice, but rather expression of these adhesion molecules is important for modulating the progression of glomerulonephritis, possibly through down-regulation of endothelial CCL2 expression.     

趋化因子在HBV感染发病中的作用

乙型肝炎是一种以局部炎性为主的感染性疾病,乙型肝炎病毒（HBV）感染宿主细胞后可诱导宿主细胞中趋化因子分泌及其受体表达,趋化因子／受体的相互作用进一步介导中性粒细胞、淋巴细胞等向炎症部位聚集,参与组织损伤;同时诱导T、B细胞分化成熟,对乙型肝炎的发展与转归、肝组织的损伤与修复有重要影响。HBV引发的慢性乙型肝炎（CHB）以Th1细胞性炎性反应为主,研究表明乙型肝炎中某些趋化因子在肝脏高表达,其受体CXCR3和CCR5在Th1细胞高表达。趋化因子尤其是CXC和CC亚家族趋化因子在趋化Th1细胞中发挥重要的作用：     

炎症-肿瘤转化在眼部相关疾病中的研究进展

炎症向癌症转化的机制一直是癌症研究中的重点。作为炎症-肿瘤转化起始时所处的环境，炎性微环境是一个多种调控因子、细胞的大集合，其中包含的肿瘤干细胞、肿瘤相关巨噬细胞以及细胞因子（如趋化因子、生长因子）等在常见的眼部肿瘤中对肿瘤的起始、发生、演进乃至恶性转化和转移的过程起到了至关重要的调控作用。基于此，主要讨论了在炎性微环境中的肿瘤相关细胞、细胞因子以及细胞外基质等对肿瘤细胞的增殖、转移、浸润、侵袭过程的影响，着重探讨了眼部炎症-肿瘤转化相关的分子机制；并综述了视网膜母细胞瘤、腺样囊性癌等常见眼部肿瘤的特征及其由炎症到肿瘤发生过程中起重要调控作用的分子；最后，针对这些眼部肿瘤普遍存在的信号通路和分子靶点做出了对未来诊断及治疗方法的展望，以期在今后对眼科肿瘤的诊治过程中，能够针对提及的炎性成分设计思路，最大化防止炎症-肿瘤转化和恶性转归出现。