Rosa Penín

Epigenetic disruption of cadherin-11 in human cancer metastasis

Little is known about the molecular events occurring in the metastases of human tumours. Epigenetic alterations are dynamic lesions that change over the natural course of the disease, and so they might play a role in the biology of cancer cells that have departed from the primary tumour. Herein, we have adopted an epigenomic approach to identify some of these changes. Using a DNA methylation microarray platform to compare paired primary tumour and lymph node metastatic cell lines from the same patient, we observed cadherin‐11 promoter CpG island hypermethylation as a likely target of the process. We found that CDH11 DNA methylation‐associated transcriptional silencing occurred in the corresponding lymph node metastases of melanoma and head and neck cancer cells but not in the primary tumours. Using in vitro and in vivo cellular and mouse models for depleted or enhanced CDH11 activity, we also demonstrated that CDH11 acts as an inhibitor of tumour growth, motility and dissemination. Most importantly, the study of CDH11 5′‐CpG island hypermethylation in primary tumours and lymph node metastases of cancer patients showed this epigenetic alteration to be significantly confined to the disseminated cells. Overall, these results indicate the existence of metastasis‐specific epigenetic events that might contribute to the progression of the disease. Copyright

Progeny of Lgr5-expressing hair follicle stem cell contributes to papillomavirus-induced tumor development in epidermis.

Epidermal keratinocytes and hair follicle (HF) stem cells (SCs) expressing oncogenes are competent at developing squamous cell carcinomas (SCCs) in epidermis and HFs, respectively. To determine whether bulge and hair germ (HG) SCs from HF contribute to SCC generation at distant epidermis, the most frequent epidermal region where these lesions arise in human skin, we used a skin cancer mouse model expressing E6 and E7 oncoproteins from Human papillomavirus (HPV) 16 in SCs and basal keratinocytes. This previously described mouse model recapitulates the human skin papillomavirus-induced SCC pathology. We show that E6 and E7 expression promote the expansion of keratin 15 (K15)-expressing cells. These K15+ aberrant cells exhibit some HGSC markers and diminished expression of Tcf3 and Sox9 hair SC specification genes, which are accumulated in HFs and mislocalized to interfollicular epidermis. Leucine-rich G-protein-coupled receptor 5 (Lgr5)-expressing SCs, localized in the bulge and HG, are the origin of the expanded K15+ cell population. A large subset of the Lgr5+ SC progeny, expressing K15 and P-cadherin, is aberrantly mobilized to the upper region of HFs and the epidermis, and accumulates at E6/E7-induced pre-neoplastic lesions and epidermal tumors. These findings indicate that aberrant accumulation of altered SCs in HFs and their subsequent migration to the epidermis contribute to HPV-induced tumor development.

Lung fibrotic tenascin-C upregulation is associated with other extracellular matrix proteins and induced by TGFβ1

BackgroundIdiopathic pulmonary fibrosis (IPF) is a progressive parenchymal lung disease of unknown aetiology and poor prognosis, characterized by altered tissue repair and fibrosis. The extracellular matrix (ECM) is a critical component in regulating cellular homeostasis and appropriate wound healing. The aim of our study was to determine the expression profile of highlighted ECM proteins in IPF lungs.MethodsECM gene and protein expression was analyzed by cDNA microarrays, rt-PCR, immunohistochemistry and western-blot in lungs from idiopathic pulmonary fibrosis (IPF), hypersensitivity pneumonitis (HP), categorized as chronic (cHP) and subacute (saHP), and healthy lung tissue. Primary fibroblast cultures from normal subjects and fibrotic patients were studied to evaluate tenascin-C (TNC) synthesis.ResultsA total of 20 ECM proteins were upregulated and 6 proteins downregulated in IPF. TNC was almost undetected in normal lungs and significantly upregulated in fibrotic lungs (IPF and cHP) compared to saHP. Furthermore, it was located specifically in the fibroblastic foci areas of the fibrotic lung with a subepithelial gradient pattern. TNC levels were correlated with fibroblastic foci content in cHP lungs. Versican and fibronectin glycoproteins were associated with TNC, mainly in fibroblastic foci of fibrotic lungs. Fibroblasts from IPF patients constitutively synthesized higher levels of TNC than normal fibroblasts. TNC and α-sma was induced by TGF-β1 in both fibrotic and normal fibroblasts. TNC treatment of normal and fibrotic fibroblasts induced a non-significant increased α-sma mRNA.ConclusionsThe difference in ECM glycoprotein content in interstitial lung diseases could contribute to the development of lung fibrosis. The increase of TNC in interstitial areas of fibrotic activity could play a key role in the altered wound healing.

Cutaneous metastasis from lung cancer: Retrospective analysis of 30 patients

Lung carcinoma is one of the most frequent sources of skin metastases in male patients. Our objective was to analyse the clinical and pathological features of 30 patients with skin metastases from lung carcinoma. Cutaneous biopsies codified as ‘skin metastasis from lung carcinoma’ during 1988–2009 at Bellvitge Hospital (Barcelona, Spain) were reviewed. The histological types of 30 lung carcinomas (29 men, 1 woman) were squamous cell carcinoma (10 cases), undifferentiated carcinoma (7), adenocarcinoma (6), small cell carcinoma (5) and large cell carcinoma (2). The most frequent clinical presentation was as a solitary nodule (16 cases), and the most frequent site was the head (13 cases). Cutaneous metastases were present at the time of diagnosis of the lung primary tumour in 66% of cases. Skin biopsy might be helpful to establish the histological type of tumour, and thus help with therapeutic decision‐making. Cutaneous metastases from lung cancer remain a poor prognostic feature.

Decreased immunoreactivity for cell-cycle regulator p27Kip1 in Kaposi's sarcoma correlates with higher stage and extracutaneous involvement.

A consistent relationship has been established between the development of Kaposis sarcoma (KS) and human herpes virus‐8 (HHV8) infection. HHV8‐encoded v‐cyclin, through its complexing with cyclin‐dependent kinase 6, contributes to the phosphorylation and proteasome‐mediated degradation of p27Kip1. On the other hand, down‐regulation of p27Kip1 expression seems to facilitate metastatic dissemination in a variety of human neoplasms. Although the neoplastic nature of KS remains controversial, it has been repeatedly demonstrated that in some patients KS may behave as a malignant neoplasm and follow an ominous course, especially in HIV‐positive patients and when associated with extracutaneous involvement. To determine whether decreased p27Kip1 levels are also related to more aggressive behaviour in KS, it was decided to investigate p27Kip1 immunoreactivity in KS biopsy specimens and its possible changes in relation to cutaneous versus extracutaneous involvement and HIV serological status. Forty‐nine cases of KS (29 AIDS‐related and 21 classical) corresponding to 30 cutaneous biopsy specimens (ten macules, seven plaques, and 13 tumours) and 19 extracutaneous biopsy specimens were immunostained to determine the expression of p27Kip1 and the proliferation marker Ki‐67 antigen. The mean percentages of p27Kip1‐positive cells were significantly higher in biopsy specimens from skin lesions (77.8±21.1) than in those from extracutaneous locations (42.0±26.0). Amongst cutaneous lesions, p27Kip1 expression was significantly higher in macules (83.8±18.5) and plaques (91.4±6.4) than in tumours (65.8±22.6). Ki‐67 immunoreactivity showed no correlation with any of the variables studied. These results lend support to the hypothesis that decreased levels of p27Kip1, which may have been brought about by HHV8 infection, play a role in KS progression through its various histopathological stages, to its eventual extracutaneous spread. Copyright

Cancer Stem-like Cells Act via Distinct Signaling Pathways in Promoting Late Stages of Malignant Progression

Cancer stem-like cells (CSC) play key roles in long-term tumor propagation and metastasis, but their dynamics during disease progression are not understood. Tumor relapse in patients with initially excised skin squamous cell carcinomas (SCC) is characterized by increased metastatic potential, and SCC progression is associated with an expansion of CSC. Here, we used genetically and chemically-induced mouse models of skin SCC to investigate the signaling pathways contributing to CSC function during disease progression. We found that CSC regulatory mechanisms change in advanced SCC, correlating with aggressive tumor growth and enhanced metastasis. β-Catenin and EGFR signaling, induced in early SCC CSC, were downregulated in advanced SCC. Instead, autocrine FGFR1 and PDGFRα signaling, which have not been previously associated with skin SCC CSC, were upregulated in late CSC and promoted tumor growth and metastasis, respectively. Finally, high-grade and recurrent human skin SCC recapitulated the signaling changes observed in advanced mouse SCC. Collectively, our findings suggest a stage-specific switch in CSC regulation during disease progression that could be therapeutically exploited by targeting the PDGFR and FGFR1 pathways to block relapse and metastasis of advanced human skin SCC.

Merkel Cell Carcinoma: Differences between Sun-Exposed and Non-Sun-Exposed Variants - A Clinical Analysis of 36 Cases

Background: There are few studies focusing on the clinical characteristics of Merkel cell carcinoma (MCC). Objective: To retrospectively analyze the clinical features of our patients and their relationship with sun exposure. Methods: Thirty-six patients diagnosed with MCC (20 men and 16 women, mean age 72.08 years) were included in the study. Results: 21 patients developed MCC in sun-exposed skin and 15 patients in non-sun-exposed areas. MCC was >2 cm in 19 cases. Six of the 7 patients who died as a result of MCC had non-sun-exposed tumors. Only tumor size >2 cm significantly influenced survival (p = 0.033). Conclusion: Sun-exposed lesions tended to be <2 cm in diameter and were more common in men, while non-sun-exposed tumors were larger, usually occurring in women and carrying a greater likelihood of death by MCC. Non-sun-exposed tumors usually present as fast-growing, multilobar nodular lesions with a smooth shiny surface.

Systemic and Pulmonary Vascular Remodelling in Chronic Obstructive Pulmonary Disease

Background Chronic Obstructive Pulmonary Disease (COPD) is associated with subclinical systemic atherosclerosis and pulmonary vascular remodelling characterized by intimal hyperplasia and luminal narrowing. We aimed to determine differences in the intimal thickening of systemic and pulmonary arteries in COPD subjects and smokers. Secondary aims include comparisons with a non-smokers group; determining the clinical variables associated with systemic and pulmonary intimal thickening, and the correlations between systemic and pulmonary remodelling changes. Methods All consecutive subjects undergoing lung resection were included and divided into 3 groups: 1) COPD, 2) smokers, and 3) non-smokers. Sections of the 5th intercostal artery and muscular pulmonary arteries were measured by histo-morphometry. Four parameters of intimal thickening were evaluated: 1) percentage of intimal area (%IA), 2) percentage of luminal narrowing, 3) intimal thickness index, and 4) intima-to-media ratio. Results In the adjusted analysis, the systemic arteries of COPD subjects showed greater intimal thickening (%IA) than those of smokers (15.6±1.5% vs. 14.2±1.6%, p = 0.038). In the pulmonary arteries, significant differences were observed for %IA between the 2 groups (37.3±2.2% vs. 29.3±2.3%, p = 0.016). Among clinical factors, metabolic syndrome, gender and COPD status were associated with the systemic intimal thickening, while only COPD status was associated with pulmonary intimal thickening. A correlation between the %IA of the systemic and pulmonary arteries was observed (Spearman’s rho = 0.46, p = 0.008). Conclusions Greater intimal thickening in systemic and pulmonary arteries is observed in COPD patients than in smokers. There is a correlation between systemic and pulmonary vascular remodelling in the overall population.

Vascular disease in COPD: systemic and pulmonary expression of PARC (Pulmonary and Activation-Regulated Chemokine)

Introduction The role of Pulmonary and Activation-Regulated Chemokine (PARC) in the physiopathology of Chronic Obstructive Pulmonary Disease (COPD) is not fully understood. The aim of the present study is to analyze the expression of PARC in lung tissue and its relationship with the vascular remodeling of the systemic and pulmonary arteries of COPD subjects. Methods To achieve this objective, protein and gene expression experiments, together with ELISA assays, were performed on the lung tissue, intercostal arteries and serum samples from COPD patients, non-obstructed smokers (NOS) and never-smokers (NS). Results A total of 57 subjects were included in the analysis (23 COPD, 18 NOS and 16 NS). In the comparisons between groups, a significantly increased lung protein expression of PARC was observed in the COPD group compared to the NOS group (1.96±0.22 vs. 1.29±0.27, P-adjusted = 0.038). PARC was located predominantly in the smooth muscle cells of the remodeled pulmonary muscular arteries and the macrophage-rich area of the alveolar parenchyma. No differences were detected in PARC gene expression analyses. The protein content of PARC in the intercostal arteries were similar between groups, though little remodeling was observed in these arteries. Circulating levels of PARC were numerically higher in patients with COPD compared to NOS and NS. Conclusion The results of the present study suggest an increased lung protein expression of PARC in COPD subjects. This protein was mainly localized in the smooth muscle cells of the pulmonary muscular arteries and was associated with the severity of intimal thickening, indicating its possible role in this remodeling process.

Histopathological Features of Orofacial Granulomatosis.

Abstract:Orofacial granulomatosis (OFG) is characterized by granulomatous inflammation in the orofacial region. Although several series have been reported, biopsy has not been performed in all cases and the histopathological features have not been extensively evaluated. Our purpose was to analyze the histopathological features of our patients with OFG. Twenty-two patients diagnosed with OFG at Bellvitge Hospital (Barcelona, Spain) from 1985 to 2010 were included in the study. All of our patients (14 men and 8 women; mean age 46.77 years, SD 13.61) presented with labial swelling, involving the upper lip in 13 cases and the lower lip in 9 at presentation. Fissured tongue was observed in 9 cases. Three patients suffered facial palsy. Granulomas were observed in 16 patients. All patients showed a perivascular, lymphohistiocytic inflammatory infiltrate with prominent plasma cells in 21 cases. In 5 cases, mast cells were easily observed. In 13 patients, an interstitial infiltrate was also present. All cases showed dilated lymphatic channels, and 19 edema of the lamina propria or the dermis. Perilymphatic granulomas were observed in 12 cases, intralymphatic granulomas in 2, and intralymphatic histiocytes in 2. In conclusion, loose epithelioid cells or lymphonodular granulomas were observed in 73% of our patients. Although none of our patients developed Crohn disease, OFG is histopathologically similar to cutaneous lesions of Crohn disease. The perilymphatic disposition of granulomas and the presence in some cases of intralymphatic histiocytes or intralymphatic granulomas may explain the dilatation of lymphatic vessels and the development of edema.