ABSTRACT
Chemokine receptors are known to regulate homing of lymphocytes into secondary lymphoid organs and may also be involved in the lymphatic spread of solid tumors. Therefore, the assessment of chemokine receptor expression on colorectal carcinomas could potentially improve the prediction of lymph node spread. This is of great importance for the selection of patients for local therapy without the need for concomitant lymphatic dissection. Currently, only 5% of all patients can be selected for this desirable treatment option by established prognosticators. In a retrospective study, expression levels of the chemokine receptors CCR7, CXCR4 and CXCR5 were determined by immunohistochemistry on paraffin-embedded specimens of 99 colorectal carcinomas, which were curatively operated on, comprising all stages of the disease. Receptor expressions (absent vs. positive) from the overall tumor (OT) and from the invasion front (IF) including further prognosticators were correlated with lymph node status by uni- and multivariate analysis. Data were also correlated with synchronous distant metastases and overall survival. Median follow-up was 64 months. In univariate analysis, lymph node status correlated significantly with lymphovascular invasion, the expression of CCR7 IF, CCR7 OT, CXCR4 IF and CXCR4 OT, as well as pT category. Multivariate analysis revealed a significant correlation of lymph node status with lymphovascular invasion and CCR7 IF expression level. Most interestingly, CCR7 IF expression was significantly linked to decreased survival. CCR7 plays an important role in the mechanism of lymph node spread in colorectal carcinoma. Evaluation of the chemokine receptor expression profile seems to be appropriate to improve the selection of patients suited for local treatment and might constitute targets for nonsurgical therapy.
Subject(s)
Colorectal Neoplasms/pathology , Receptors, Chemokine/analysis , Adult , Aged , Aged, 80 and over , Colorectal Neoplasms/chemistry , Colorectal Neoplasms/mortality , Female , Humans , Lymphatic Metastasis , Male , Middle Aged , Multivariate Analysis , Neoplasm Invasiveness , Prognosis , Receptors, CCR7 , Receptors, CXCR4/analysis , Retrospective StudiesABSTRACT
The CC chemokine receptor CCR7 has been identified as a key regulator of homeostatic B and T cell trafficking to secondary lymphoid organs. Data presented here demonstrate that CCR7 is also an essential mediator for entry of both dermal and epidermal dendritic cells (DC) into the lymphatic vessels within the dermis while this receptor is dispensable for the mobilization of Langerhans cells from the epidermis to the dermis. Moreover, a distinct population of CD11c(+)MHCII(high) DC showing low expression of the costimulatory molecules CD40, CD80, and CD86 in wild-type animals was virtually absent in skin-draining lymph nodes of CCR7-deficient mice under steady-state conditions. We provide evidence that these cells represent a semimature population of DC that is capable of initiating T cell proliferation under conditions known to induce tolerance. Thus, our data identify CCR7 as a key regulator that governs trafficking of skin DC under both inflammatory and steady-state conditions.
Subject(s)
Cell Movement/physiology , Dendritic Cells/metabolism , Inflammation/metabolism , Receptors, Chemokine/metabolism , Animals , CD11c Antigen/immunology , CD11c Antigen/metabolism , Cell Division/immunology , Cell Movement/immunology , Dendritic Cells/immunology , Histocompatibility Antigens Class II/immunology , Histocompatibility Antigens Class II/metabolism , Inflammation/immunology , Langerhans Cells/immunology , Langerhans Cells/metabolism , Mice , Receptors, CCR7 , Receptors, Chemokine/deficiency , Receptors, Chemokine/genetics , T-Lymphocytes/immunologyABSTRACT
Homeostatic chemokines participate in the development of secondary lymphoid organs and later on in the functional organization of these tissues. The development of lymph nodes (LNs) and Peyer's patches depends on the recruitment of CD3- CD4+ interleukin (IL)-7R alpha hi cells to sites of future organ development. CD3- CD4+ IL-7R alpha hi cells express the chemokine receptor CXCR5 and might be attracted by its ligand CXCL13, which is secreted by mesenchymal cells. Mesenchymal cells also secrete CCL19, a ligand for CCR7, yet it is not clear whether CCR7 and CCL19 are important for secondary lymphoid organ development. Analyzing CXCR5-/- CCR7-/- double deficient mice we now show that these mice lack all examined peripheral LNs suggesting a profound role for both receptors in secondary lymphoid organ development. We demonstrate that CD3- CD4+ IL-7R alpha hi cells express CXCR5 as well as CCR7 indicating that both receptors cooperate during an early step of secondary lymphoid organ development. Furthermore, CXCR5-/- CCR7-/- mice display a severely disturbed architecture of mesenteric LN and spleen. Due to an impaired migration of B cells into the white pulp, CXCR5-/- CCR7-/- mice fail to develop B cell follicles but show small clusters of unorganized lymphocytes in the spleen. These data demonstrate a cooperative function of CXCR5 and CCR7 in lymphoid organ organogenesis and organization.
