No abstract

Chemokines and their receptors are involved in tumourigenicity and clinicopathological significance of chemokines receptor expression in pancreatic adenocarcinoma (PA) is not fully understood. This study was conducted to determine patients' outcome according to the expressions of CXCR4, CXCR7 and HIF-1a after resection of PA. Immunohistochemistry for CXCR4, CXCR7 and HIF-1a expressions as well as cell proliferative index (Ki-67) was conducted in 71 resected (R0) PA and their 48 related lymph nodes (LN) using tissue microarray. CXCR4 and CXCR7 expressions were positively correlated to HIF-1a suggesting a potential role of HIF-1a in CXCR4 and CXCR7 transcription activation. Patients with CXCR4 high tumour expression had shorter OS than those with low expression (median survival: 9.7 vs 43.2 months, P ¼ 0.0006), a higher risk of LN metastases and liver recurrence. In multivariate analysis, high CXCR4 expression, LN metastases and poorly differentiated tumour are independent negative prognosis factors. In a combining analysis, patients with CXCR4 low /CXCR7 low tumour had a significantly shorter DFS and OS than patients with a CXCR7 high /CXCR4 high tumour. CXCR4 in resected PA may represent a valuable prognostic factor as well as an attractive target for therapeutic purpose.

To probe the potential contribution of ␤-galactoside-contributing epitopes and receptor proteins (gal-1 and gal-3) to colon malignancy, we first examined the expression of galectins and binding sites in clinical specimens by lectin and immunohistochemistry. Sixty-seven colonic surgical resections were studied, including 10 normal, 10 mild dysplasias, 10 severe dysplasias and 37 cancers. gal-1 and gal-3 were expressed in variable amounts in the epithelial cells and the connective tissue of normal colon. Their expression significantly increased with the degree of dysplasia, suggesting that gal-1 and gal-3 and their binding sites are related to malignant progression, while gal-8 has been associated with suppressor activity. To study the functional aspects, the influence of these galectins on the migration of 4 human colorectal cancer cell lines (HCT-15, LoVo, DLD-1, CoLo201) was studied. In agreement with histopathologic monitoring, these tumor cells were found to produce gal-3, while only Cell-surface epitopes have a conspicuous bearing on cellular features associated with malignancy. The concept that glycans of surface glycoconjugates can function in information storage and transfer by forming a sugar code 1 is supported by the rather ubiquitous presence of endogenous lectins. Since they are located at branch ends, ␤-galactoside-containing epitopes are spatially accessible for such an interaction. This point and the elaborate enzymatic machinery producing these epitopes imply functional relevance of these glycan sections. A complete family of endogenous lectins act as receptors for ␤-galactosides and derivatives; they are referred to as galectins and are involved in the various aspects of tumor biology, including invasion and metastasis. [2][3][4][5][6][7][8] The members of this family share a jelly roll-like folding and a common topology of the CRD with high-sequence homology scores in intermammal comparison, secretion via a nonclassical pathway and interaction with the extracellular glycans of laminins, fibronectins, integrins and other cell-surface components. 4 -9 With respect to colon tumor biology, gal-1 and gal-3 have been investigated histopathologically with different methods and reagents, yielding conflicting results on correlations with tumor progression. 4,10 -12 Two reports on transfected cells and tissue sections underscore the potential relevance of gal-3 for colon cancer metastasis. 10,13 However, the prototype (homodimeric) gal-1 is encountered less frequently in colon cancer. 11,14,15 This indication of functional divergence prompted us to extend the histopathologic monitoring and to use cell models to test in vitro if and to what extent these 2 galectins influence cell migration. Interestingly, the tandem-repeat-type gal-8 has previously been shown to display the features of a tumor suppressor based on cell-migration measurements and immunologic monitoring of expression. 16 Thus, our aims were to shed further light on the role of gal-1 and gal-3 in the biology of human colon cancers, to presen...

Background and aims: Galectins are β-galactoside binding proteins. This ability may have a bearing on cell adhesion and migration/proliferation in human colon cancer cells. In addition to galectins-1 and -3 studied to date, other members of this family not investigated in detail may contribute to modulation of tumour cell features. This evident gap has prompted us to extend galectin analysis beyond the two prototypes. The present study deals with the quantitative determination of immunohistochemical expression of galectin-8 in normal, benign, and malignant human colon tissue samples and in four human colon cancer models (HCT-15, LoVo, CoLo201, and DLD-1) maintained both in vitro as permanent cell lines and in vivo as nude mice xenografts. The role of galectin-8 (and its neutralising antibody) in cell migration was investigated in HCT-15, LoVo, CoLo201, and DLD-1 cell lines. Methods: Immunohistochemical expression of galectin-8 and its overall ability to bind to sugar ligands (revealed glycohistochemically by means of biotinylated histochemically inert carrier bovine serum albumin with α-and β-D-galactose, α-D-glucose, and lactose derivatives as ligands) were quantitatively determined using computer assisted microscopy. The presence of galectin-8 mRNA in the four human colon cancer cell lines was examined by reverse transcriptase-polymerase chain reaction. In vitro, cellular localisation of exogenously added galectin-8 in the culture media of these colon cancer cells was visualised by fluorescence microscopy. In vitro galectin-8 mediated effects (and the influence of its neutralising antibody) on migration levels of living HCT-15, LoVo, CoLo201, and DLD-1 cells were quantitatively determined by computer assisted phase contrast microscopy. Results: A marked decrease in immunohistochemical expression of galectin-8 occurred with malignancy development in human colon tissue. Malignant colon tissue exhibited a significantly lower galectin-8 level than normal or benign tissue colon cancers; those with extensive invasion capacities (T3-4/N+/M+) harboured significantly less galectin-8 than colon cancers with localised invasion capacities (T1-2/N0/M0). The four experimental models (HCT-15, LoVo, CoLo201, and DLD-1) had more intense galectin-8 dependent staining in vitro than in vivo. Grafting the four experimental human colon cancer models onto nude mice enabled us to show that the immunohistochemical expression of galectin-8 was inversely related to tumour growth rate. In vitro, galectin-8 reduced the migration rate of only those human experimental models (HCT-15 and CoLo201) that exhibited the lowest growth rate in vivo. Conclusions: Expression of galectin-8 correlated with malignancy development, with suppressor activity, as shown by analysis of clinical samples and xenografts. In vitro, only the two models with low growth rates were sensitive to the inhibitory potential of this galectin. Future investigations in this field should involve fingerprinting of these newly detected galectins, transcending the common focus o...

Experimental T-cell-mediated hepatitis induced by concanavalin A (Con A) involves the production of different cytokines and chemokines and is characterized by leukocyte infiltration. Because the chemokine receptor CCR5 and its ligands (CCL3, CCL4, and CCL5) regulate leukocyte chemotaxis and activation, we investigated the role of CCR5 during Con A-induced liver injury. Serum levels of CCR5 ligands and their hepatic transcript levels were significantly increased after Con A injection, whereas CCR5 ؉ liver mononuclear cells were recruited to the liver. CCR5-deficient (CCR5 ؊/؊ ) mice disclosed increased mortality and liver injury following Con A administration compared with wild-type mice. CCR5 ؊/؊ mice also exhibited increased production of interleukin 4, tumor necrosis factor ␣, CCL3, CCL4, and CCL5, and a prominent liver mononuclear cell infiltrate, among which many cells were CCR1 ؉ . In vivo neutralization of CCR5 ligands in CCR5 ؊/؊ mice afforded a protection against hepatitis only when CCL5 was neutralized. In conclusion, CCR5 deficiency exacerbates T-cell-mediated hepatitis, and leads to increased levels of CCR5 ligands and a more pronounced liver mononuclear infiltrate, suggesting that CCR5 expression can modulate severity of immunomediated liver injury. (HEPATOLOGY 2005;42:854-862.)