title: Analysis of the expression of HLA class I, proinflammatory cytokines and chemokines in primary tumors from patients with localized and metastatic renal cell carcinoma.
abstract: Changes in the human leukocyte antigen (HLA) class I expression and cytokine and chemokine production both by cancer cells and by normal surrounding tissue are believed to be responsible for immune escape and tumor progression. In this study, we compared the tumor expression levels of HLA heavy chain (HLAhc), beta-2-microglobulin (beta2m), chemokines (Interferon-gamma-inducible Protein-10 (IP-10), Interferon-inducible T-cell Alpha-Chemoattractant (I-TAC), Stromal cell-Derived Factor-1 (SDF-1), Macrophage Inflammatory Protein-1-alpha (MIP-1-alpha) and Regulated upon Activation, Normally T-Expressed, and presumably Secreted (RANTES)) and cytokines (Vascular Endothelial Growth Factor (VEGF), Interferon-gamma (IFN-gamma), Interleukin-10 (IL-10), Tumor Growth Factor-beta (TGB-beta)) in primary tumors and adjacent normal tissues from patients with localized and metastatic renal cell carcinoma (RCC) using a quantitative real-time polymerase chain reaction technique. We report that the expression of HLAhc, beta2m and the studied cytokines and chemokines (except for SDF-1) was significantly higher in the tumor (29 samples) than in the normal tissue (14 samples). When we compared the tumor expression levels between patients with localized RCC and patients with advanced metastatic stage, we found that the messenger RNA expression levels of HLAhc and beta2m were much lower in patients with metastatic RCC (6 cases) than in patients with localized cancer (23 cases), with levels similar to those in normal tissue. This was also confirmed on a protein level by immunohistological labeling of tumor tissues. Thirty-nine percent of the analyzed RCC tumors showed partial loss of HLA class I molecules, while 6% of the tumors showed HLA class I total loss. The expression of IP-10, SDF-1 and VEGF-c was also significantly lower in patients with advanced tumor, while the IFN-gamma expression in metastatic RCC was not detectable. Our findings show that primary RCC tumors are characterized by a high expression of HLAhc and a presence of proinflammatory mediators and chemokines. We also observed that disease progression and development of metastasis in RCC are associated with decreased expression of HLAhc, beta2m, IP-10, SDF-1 and IFN-gamma. This microenvironment may suppress the cytotoxic response, creating conditions that favor tumor escape and cancer progression.
authors.affiliation: Servicio de Analisis Clinicos, Hospital Universitario Virgen de las Nieves, University of Granada, Avenida de las Fuerzas Armadas s/n, 18014 Granada, Spain.
authors.forename: J M
authors.initials: JM
authors.lastname: Romero
authors.forename: N
authors.initials: N
authors.lastname: Aptsiauri
authors.forename: F
authors.initials: F
authors.lastname: Vazquez
authors.forename: J M
authors.initials: JM
authors.lastname: Cozar
authors.forename: J
authors.initials: J
authors.lastname: Canton
authors.forename: T
authors.initials: T
authors.lastname: Cabrera
authors.forename: M
authors.initials: M
authors.lastname: Tallada
authors.forename: F
authors.initials: F
authors.lastname: Garrido
authors.forename: F
authors.initials: F
authors.lastname: Ruiz-Cabello
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002292:Carcinoma, Renal Cell / Q000737:chemistry / Q000276:immunology* / Q000473:pathology* / Q000556:secondary; D018925:Chemokines / Q000032:analysis* / Q000096:biosynthesis / Q000502:physiology; D016207:Cytokines / Q000032:analysis / Q000096:biosynthesis / Q000502:physiology; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000032:analysis* / Q000096:biosynthesis / Q000502:physiology; D006801:Humans; D018836:Inflammation Mediators / Q000032:analysis / Q000502:physiology*; D007680:Kidney Neoplasms / Q000737:chemistry / Q000276:immunology* / Q000473:pathology*; D008297:Male; D008875:Middle Aged
chemical_list: D018925:Chemokines; D016207:Cytokines; D015395:Histocompatibility Antigens Class I; D018836:Inflammation Mediators