Prostate Cancer Tumor Stroma: Responsibility in Tumor Biology, Diagnosis and Treatment.

Prostate cancer (PCa) is a common cancer among males globally, and its occurrence is growing worldwide. Clinical decisions about the combination of therapies are becoming highly relevant. However, this is a heterogeneous disease, ranging widely in prognosis. Therefore, new approaches are needed based on tumor biology, from which further prognostic assessments can be established and complementary strategies can be identified. The knowledge of both the morphological structure and functional biology of the PCa stroma compartment can provide new diagnostic, prognostic or therapeutic possibilities. In the present review, we analyzed the aspects related to the tumor stromal component (both acellular and cellular) in PCa, their influence on tumor behavior and the therapeutic response and their consideration as a new therapeutic target.

Expression and Clinical Significance of Metalloproteases and Their Inhibitors by Endothelial Cells From Invasive Breast Carcinomas.

BACKGROUND: Given that tumor blood vessels are important in tumor progression and metastasis, tumor endothelial cells (ECs) are the main targets of antiangiogenic therapy. The aim of the present work was to evaluate the phenotype of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) from ECs at the tumor center and its relationship to MMP/TIMP global expression and its relationship to the occurrence of distant metastasis. PATIENTS AND METHODS: An immunohistochemical study was performed using tissue arrays and specific antibodies against MMPs (MMP-2, -7, -9, -11, -13, and -14) and TIMPs (TIMP-1, -2, and -3) at the tumor center in 104 patients with primary ductal invasive breast tumors. RESULTS: MMP-11 expression by ECs was related to shorter relapse-free survival, whereas TIMP-3 expression was related to low occurrence of distant metastasis. In addition, MMP-11 and TIMP-2 expression by ECs was associated with shorter overall survival, whereas TIMP-3 expression by ECs was associated with longer overall survival. Our findings indicate significant relationships between the expression of MMPs/TIMPs by ECs and the global expression of these factors at the tumor scene. CONCLUSION: High MMP/TIMP expression by ECs from breast carcinomas, which may be consequence of the cross-talk between tumor cells and their surrounding microenvironment.

Analysis of the expression of interleukins, interferon ß, and nuclear factor-κ B in prostate cancer and their relationship with biochemical recurrence.

There are accumulating epidemiological, experimental, and genetic data supporting that prostate inflammation may contribute to prostate carcinogenesis, and several inflammatory-related molecules have been linked to tumorigenesis and prognosis in several tumors. The aim of this study was to evaluate tumor expression of inflammatory-related factors in prostate carcinomas and their possible relationship with biochemical recurrence (elevation of prostate-specific antigen serum levels). An immunohistochemical study was conducted using tissue microarrays and specific antibodies against interleukin-1ß (IL-1ß), IL-6, IL-10, IL-17, interferon ß (IFNß), and nuclear factor-κ B (NF-κB). Determinations in cancer specimens from 118 patients with primary prostate cancer (78 without and 40 with recurrence during the follow-up period) were performed. Immunostaining for all the studied proteins was localized both in tumor cells and in stromal cells in the majority of tumors. High-score values for IL-1ß or low-score values for IFNß were significantly associated with biochemical recurrence. The analysis defined a score value of 160 for IL-1ß and of 170 for IFNß as the optimal cutoff points that identified 32.7% and 73.2% of patients, respectively, having high probability of biochemical recurrence. Multivariate analysis according to a Cox model indicated that the cutoff point 170 for IFNß (P=0.035) was an independent factor associated with biochemical recurrence in patients with prostate cancer. Both IL-1ß and IFNß may be new biomarkers to distinguish high-risk/low-risk patients with prostate cancer, and to select appropriate therapeutic approaches.

Prediction of metastatic breast cancer in non-sentinel lymph nodes based on metalloprotease-1 expression by the sentinel lymph node.

AIMS: Sentinel lymph node (SLN) biopsy is the current standard axillary approach for patients with clinically node-negative breast cancer. If the SLN is positive, is still also standard in most centres to proceed with a complete axillary dissection to predict the remaining nodes affectation, despite of SLN is the only positive lymph node in 50-68% of cases. If we could identify them, these patients could be spared a complete axillary dissection. METHODS: Elevated expression of specific matrix metalloproteases (MMPs) and their inhibitors (TIMPs) by stromal mononuclear inflammatory cells (MICs) of primary tumours is significantly associated with distant metastasis development in breast cancer. In the present study we first identified candidate MMPs/TIMPs associated with axillary metastasis in a preliminary group (n=50), and subsequently examined the potential of their expression in the SLN for predicting the status of the remaining nodes, in 105 patients with intraoperative SLN-assessment. RESULTS: MMP-1 expression by MICs from SLNs was significantly associated with metastatic spread to non-SLNs. Moreover, in all cases with negative MMP-1 expression by MICs from SLNs, the remaining non-SLNs were not affected (p<0.0001). Therefore, we demonstrate that MMP-1 expression by MICs from SLNs had 100% sensitivity, 100% negative-predictive value and 61.5% specificity to predict non-SLNs status. CONCLUSION: This is the first time that tumour spread to the remaining axillary nodes has been predicted from molecular features of the SLN(s). If confirmed in larger studies, patients could be spared the morbidity associated with an unnecessary complete lymphadenectomy.

Low plasma levels of monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-alpha (TNFalpha), and vascular endothelial growth factor (VEGF) in patients with alpha1-antitrypsin deficiency-related fibromyalgia.

Abnormalities in blood inflammatory markers have been associated with clinical manifestations and the pathogenesis of the fibromyalgia syndrome (FMS); a relationship between inherited alpha1-antitrypsin deficiency (AATD) and FMS has also been recently raised. In this study, plasma levels of inflammatory markers in FMS patients with and without AATD have been investigated. Blood samples from 138 age-matched females (79 FMS) and 59 general population (GP), with normal MM [n = 82 (59.4%)] and with MS, MZ, SZ, and ZZ AATD genotypes [n = 56 (40.6%)], were analyzed by ELISA for monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-alpha (TNFalpha), soluble TNFalpha receptors I and II, interleukin-8, and vascular endothelial growth factor (VEGF). Plasma levels of MCP-1, VEGF, and TNFalpha were significantly lower in FMS and GP subjects with AATD compared with those with normal MM-AAT genotypes. Moreover, plasma levels of MCP-1, VEGF, and TNFalpha were lower in AATD subjects with FMS than in those without FMS (P = 0.000, 0.000, and 0.046, respectively). No statistical differences were found for the other substances measured. Furthermore, a logistic regression model based on plasma MCP-1 cutoff value of