Pilar Martínez-Onsurbe

MAP Kinases and Prostate Cancer

The three major mitogen-activated protein kinases (MAPKs) p38, JNK, and ERK are signal transducers involved in a broad range of cell functions including survival, apoptosis, and cell differentiation. Whereas JNK and p38 have been generally linked to cell death and tumor suppression, ERK plays a prominent role in cell survival and tumor promotion, in response to a broad range of stimuli such as cytokines, growth factors, ultraviolet radiation, hypoxia, or pharmacological compounds. However, there is a growing body of evidence supporting that JNK and p38 also contribute to the development of a number of malignances. In this paper we focus on the involvement of the MAPK pathways in prostate cancer, including the less-known ERK5 pathway, as pro- or antitumor mediators, through their effects on apoptosis, survival, metastatic potential, and androgen-independent growth.

Role of IAPs in prostate cancer progression: immunohistochemical study in normal and pathological (benign hyperplastic, prostatic intraepithelial neoplasia and cancer) human prostate

BackgroundIn this study was investigate IAPs in normal human prostate (NP), benign prostatic hyperplasia (BPH), prostatic intraepithelial neoplasia (PIN) and prostatic carcinoma (PC), and their involvement in apoptosis/proliferation via NF-kB (TNF-α, IL-1) stimulation.MethodsImmunohistochemical and Western blot analyses were performed in 10 samples of normal prostates, 35 samples of BPH, 27 samples diagnosis of PIN (with low-grade PIN or high-grade PIN) and 95 samples of PC (with low, medium or high Gleason grades).ResultsIn NP, cytoplasm of epithelial cells were positive to c-IAP1/2 (80% of samples), c-IAP-2 (60%), ILP (20%), XIAP (20%); negative to NAIP and survivin. In BPH, epithelial cells were immunostained to c-IAP1/2 (57.57%), c-IAP-2 (57.57%), ILP (66.6%), NAIP (60.6%), XIAP (27.27%), survivin (9.1%). Whereas low-grade PIN showed intermediate results between NP and BPH; results in high-grade PIN were similar to those found in PC. In PC, epithelial cells were immunostained to c-IAP1/2, c-IAP-2, ILP, NAIP, XIAP (no Gleason variation) and survivin (increasing with Gleason).ConclusionsIAPs could be involved in prostate disorder (BPH, PIN and PC) development since might be provoke inhibition of apoptosis and subsequently cell proliferation. At the same time, different transduction pathway such as IL-1/NIK/NF-kB or TNF/NF-kB (NIK or p38) also promotes proliferation. Inhibitions of IAPs, IL-1α and TNFα might be a possible target for PC treatment since IAPs are the proteins that inhibited apoptosis (favour proliferation) and IL-1α and TNFα would affect all the transduction pathway involucrate in the activation of transcription factors related to survival or proliferation (NF-kB, Elk-1 or ATF-2).

Aspiration Cytology of 147 Adnexal Cysts with Histologic Correlation

OBJECTIVE To assess the usefulness of cytology in the diagnosis of 147 histologically established adnexal cysts. STUDY DESIGN Retrospective, macro-microscopic study based on fluid aspirated from 132 ovarian and 15 extraovarian cysts and projected as a cytohistologic correlation. RESULTS Typical macroscopic features were identified in 76% of endometriotic cysts, in 53% of mucinous neoplasms and in 67% of dermoid cysts. Cytology helped to identify 67% of nonneoplastic and 56% of neoplastic cysts. The lowest diagnostic sensitivities were observed in functional cysts and benign serous neoplasms (50%), while the highest were shown by endometriotic cysts (76%) and malignant epithelial neoplasms (71%). Inadequate samples were obtained from all types of cysts, even malignant ones (two mucinous cystadenocarcinomas). Diagnostic cytology was useless in extraovarian cysts (33% sensitivity). An adult granulosa cell tumor was erroneously diagnosed as a follicular cyst by cytologic examination. CONCLUSION Examination of the cyst fluids obtained by aspiration demonstrated low sensitivity, with 43% of inadequate samples obtained from all types of cysts. Malignant cystic neoplasms may be overlooked in inadequate samples. Our study also revealed that specificity in this type of analysis is high in inadequate samples, provided that the technique is carried out correctly.

Clinical significance of both tumor and stromal expression of components of the IL-1 and TNF-α signaling pathways in prostate cancer

IL-1 and TNF-α, the two major proinflammatory cytokines, have been involved in initiation and progression of several malignancies. They could influence the biological behavior of prostatic tumors and patient outcome, and could be useful as prognostic factors. This study evaluated the prognostic capability for biochemical progression after radical prostatectomy of expression of IL-1, TNF-α and related signaling components, in the tumor and surrounding stroma, as well as its correlation with other clinicopathological features. Expression of IL-1α, IL-1β, IL-1Ra, IL-1RI, IL-1RII, IRAK-1, TRAF6, TNF-α, TNFRI and TRAF2 was analyzed by immunohistochemistry in radical prostatectomy samples from 93 prostate cancer patients. Spearmans test, Kaplan-Meier curves, and univariate and multivariate Cox proportional hazard regression analyses were performed. Expression of TNF-α, TNFRI, TRAF2, ILRI, IRAK-1 and TRAF6 correlated with at least one clinicopathological feature (clinical T stage, pathological T stage, preoperative serum PSA or Gleason score). Increased tumor expression of TNF-α, TNFRI and IL-1RI, and reduced tumor expression of IRAK-1 were significantly correlated with a poor prognosis in univariate analysis. Reduced stromal expression of IL-1β and IL-1RII, and increased stromal expression of IRAK-1 were also adverse prognostic factors in univariate analysis. Remarkably, tumor IL-1β and stromal IL-1RII and IRAK-1 remained as independent prognostic factors after adjustment for preoperative serum PSA, pathological T stage and Gleason score in multivariate Cox models. Our results suggest that prostatic expression of TNF-α, IL-1β and related signaling proteins (TNFRI, IL-1RI, IL-1RII and IRAK-1) predicts clinical outcome in prostate cancer, and support the involvement of TNF-α and IL-1β signaling in prostate cancer progression.

Relationship between IL-6/ERK and NF-κB: a study in normal and pathological human prostate gland

BACKGROUND There is growing evidence that inflammation is a causal factor in cancer, where pro-inflammatory cytokines such as IL-6, IL-1 or TNF-α could induce cellular proliferation by activation of NF-κB. This study focuses on the IL-6/ERK transduction pathway, its relationship with NF-κB, and the consequences of dysregulation in the development of prostate pathologies such as benign prostate hyperplasia (BPH), prostate intraepithelial neoplasia (PIN) and prostate cancer (PC). METHODS Immunohistochemical and Western blot analyses for IL-6, gp-130, Raf-1, MEK-1, ERK-1, p-MEK, ERK-2, p-ERK, NF-κB/p-50 and NF-κB/p-65 were carried out in 20 samples of normal prostate glands, 35 samples of BPH, 27 samples with a diagnosis of PIN (low-grade PIN or high-grade PIN), and 95 samples of PC (23 with low, 51 with medium and 21 with high Gleason scores). RESULTS Immunoreaction to IL-6, gp-130, ERK-1, ERK-2, p-ERK and NF-κB/p50 was found in the cytoplasm of epithelial cells in normal prostate samples; p-MEK was found in the nucleus of epithelial cells; but not expression to Raf-1, MEK-1 and NF-κB/p65. In BPH, all of these proteins were immunoexpressed, while there was increased immunoexpression of IL-6, gp-130, p-MEK, ERK-1, ERK-2 and NF-κB/p50 (cytoplasm). In PC, immunoexpression of IL-6 and gp-130 were similar to that found in BPH; while immunoexpression of Raf-1, MEK-1, p-MEK, ERK-1, ERK-2, p-ERK, NF-κB/p50 (nucleus and cytoplasm), and NF-κB/p65 (nucleus and cytoplasm) was higher than in BPH. CONCLUSION Translocation of NF-κB to the nucleus in PC and high-grade PIN could be stimulated by the IL-6/ERK transduction pathway, but might also be stimulated by other transduction pathways, such as TNF-α/NIK, TNF/p38, IL-1/NIK or IL-1/p38. Activation of NF-κB in PC could regulate IL-6 expression. These transduction pathways are also related to activation of other transcription factors such as Elk-1, ATF-2 or c-myc (also involved in cell proliferation and survival). PC is a heterogeneous disease, where multiple transduction pathways might alter the apoptosis/proliferation balance. Significant attention should be give to the combination of novel agents directed towards inactivation of pro-inflammatory cytokines than can disrupt tumour cell growth.

Immunoreactivity to caspase-3, caspase-7, caspase-8, and caspase-9 forms is frequently lost in human prostate tumors☆☆☆

Caspases are essential initiators and executioners of apoptosis. Changes in their expression may contribute to the development of proliferative disorders such as cancer, by altering the death-proliferation homeostatic balance. The aim of this work was to analyze the expression of a broad panel of caspases at the epithelial level in human prostate tissues to assess possible prostatic disease-related alterations. We comparatively analyzed by immunohistochemistry the expression of pro-caspase-3, pro-caspase-8, pro-caspase-9, cleaved caspase-3, cleaved caspase-8, and caspase-7, in normal and pathologic (benign hyperplasic, premalignant [high-grade intraepithelial neoplasia], and cancerous [prostate cancer]) human prostate epithelium. Expression of caspases was correlated with clinicopathologic features, including preoperative prostate-specific antigen levels, Gleason scores, and biochemical progression. Percentage of positive samples for all the analyzed caspases decreased in prostate cancer versus normal prostate epithelium. The values obtained for benign prostatic hyperplasia and high-grade intraepithelial neoplasia more qualitatively resembled those of the prostate cancer group. Our results indicate that caspase expression in prostate malignant cells is reduced in a substantial number of patients and that such an alteration occurs in the premalignant stage. Loss of caspase expression could constitute a useful marker for prostate cancer diagnosis. Therapeutic approaches aimed to recover or enhance caspase expression might be effective against prostate cancer.

Fine needle aspiration cytology of intranodal myofibroblastoma. A case report.

BACKGROUND Intranodal myofibroblastoma is a rare, primitive, mesenchymal neoplasm of the lymph nodes first described in 1989. It behaves in a benign fashion and has a great predilection for the inguinal region. CASE REPORT A 56-year-old man was referred for fine needle aspiration cytology of an inguinal lymph node. Smears were moderately cellular, with a predominant population of single, small spindle cells with no atypia. Most neoplastic cells were distributed as dissociated, single cells, with few groups. The cells showed metachromatic stromal material with a fibrillary quality. Nuclei were elongated, with pointed ends and occasional twisted forms. A remarkable finding on Papanicolaou-stained smears was hemosiderin granules. After a cytologic report of low grade spindle cell tumor, the node was excised, and a histologic and immunohistochemical diagnosis of intranodal myofibroblastoma was established. CONCLUSION Intranodal myofibroblastoma should always be considered when aspirating solitary inguinal lymph nodes. The presence of a low grade spindle cell pattern of variably dissociated cells with hemosiderin granules should lead to immunocytochemical studies. Muscle-specific actin expression in the absence of S-100 protein and vascular markers permits a more specific diagnosis.

Prognostic value of inhibitors of apoptosis proteins (IAPs) and caspases in prostate cancer: caspase-3 forms and XIAP predict biochemical progression after radical prostatectomy

BackgroundThe expression status of apoptotic regulators, such as caspases and inhibitors of apoptosis proteins (IAPs), could reflect the aggressiveness of tumors and, therefore, could be useful as prognostic markers. We explored the associations between tumor expression of caspases and IAPs and clinicopathological features of prostate cancer – clinical and pathological T stage, Gleason score, preoperative serum PSA levels, perineural invasion, lymph node involvement, surgical margin status and overall survival – and evaluated its capability to predict biochemical progression after radical prostatectomy.MethodsProtein expression of caspases (procaspase-8, cleaved caspase-8, procaspase-3, cleaved caspase-3, caspase-7 and procaspase-9) and IAPs (cIAP1/2, cIAP2, NAIP, Survivin and XIAP) was analyzed by immunohistochemistry in radical prostatectomy samples from 84 prostate cancer patients. Spearman’s test, Kaplan-Meier curves, and univariate and multivariate Cox proportional hazard regression analysis were performed.ResultscIAP1/2, cIAP2, Survivin, procaspase-8, cleaved caspase-8, procaspase-3 and caspase-7 expression correlated with at least one clinicopathological feature of the disease. Patients negative for XIAP, procaspase-3 or cleaved caspase-3 had a significantly worse prognosis. Of note, XIAP, procaspase-3 and cleaved caspase-3 were predictors of biochemical progression independent of Gleason score and pathological T stage.ConclusionsOur results indicate that alterations in the expression of IAPs and caspases contribute to the malignant behavior of prostate tumors and suggest that tumor expression of XIAP, procaspase-3 and cleaved caspase-3 may help to identify prostate cancer patients at risk of progression.

Giant cell arteritis presenting as cluster headache

New onset of headache in an elderly patient is a common presenting symptom of giant cell arteritis. Headache is usually generalized, throbbing, and continuous, with focally worse pain in the temporal or, less often, in the occipital regions.1 We report a patient with a histopathologically confirmed giant cell arteritis whose clinical manifestations mimicked those of cluster headache. Case report. A 74-year-old man without previous personal or familial history of headache was evaluated in our hospital because of a 2-month history that consisted initially of one to two attacks per day and progressed to three to four attacks per day, of severe, boring pain in the left supraorbital area that lasted 15 to 20 minutes. The pain episodes …

Expression of several cytokines in prostate cancer: Correlation with clinical variables of patients. Relationship with biochemical progression of the malignance.

Background: This work is focused on finding new markers that complement or diagnoses currently used towards improving knowledge histological and statistical aspects that allow us to predict the local stage carcinomas and to identify and understand all the factors related to the progression of this disease. Materials and methods: Prostates were obtained from: normal prostates from 20 men, diagnosis of BPH (Benign Prostatic Hyperplasia) from 35 men and prostate cancer from 86 men. We studied the behavior of cytokines that have been implicated in inflammatory processes: TNF‐alfa, IL‐6, IL‐1, EGF and TGF‐B. Expression of these cytokines and its receptors was analyzed by immunohistochemistry. Spearmans test, Kaplan‐Meier curves, univariate and multivariate Cox proportional hazard regression analyses were performed. Results: Spearmans analysis showed that there was at least one correlation between TGFB‐B, IL‐6, gp‐130, IL‐1B, IL‐1R, IL‐1RII and clinic pathological feature (preoperative serum PSA, clinical t stage, pathological t stage, positive surgical margins, biochemical progression, survival). Immunostaining score was correlated with some of the clinicopathological feature. In Cox multivariate analysis between the prognostic variables (pathological T stage, Gleason score and lymph node) and immunohistochemical parameters (TGF‐B, IL‐1a, intensity TGFBRI and intensity TGFBRII) only the expression of IL‐1a was retained as independent predictors of biochemical progression after radical prostatectomy. Conclusions: Our results suggest a role for prostatic expression of TGF‐B, IL‐1a, TGFBRI and TGFBRII as prognostic markers for prostate cancer. The rational combination of novel agents directed toward the inactivation of TGF‐B, IL‐1a, TGFBRI and TGFBRII could disrupt complementary tumor cell proliferation pathways. HighlightsIn PC TNF‐&agr;, EGF, IL‐1&agr;, IL‐1RII and IL‐1Ra were observed in epithelial cells.Increased EGFR and reduced IL‐1&agr;/TGF‐B correlated with biochem. progression.IL‐1&agr; and intensity TGFBRI predicted biochemical progression.Expression of TGF‐B, IL‐1&agr;, TGFBRI and TGFBRII as prognostic markers for PC.