DigitalUM :: Browsing by Subject "Metastasis"

Browsing by Subject "Metastasis"

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Open Access
A redefinition of prognosis: Invasive carcinoma with metastasis originating from microglandular adenosis
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2026) Xiaochun Fei; Dan Chen; Biología Celular e Histología
Aim. To investigate the clinicopathological features, immunophenotype, diagnosis, and prognosis of invasive carcinoma originating from microglandular adenosis. Methods. Two cases of invasive carcinoma originating from microadenosis were analyzed in the Department of Pathology of the Ruijin Hospital affiliated with the Medical College of Shanghai Jiaotong University. Histopathological morphology, immuno-histochemical staining, and prognosis were observed. Results. (1) Histopathological morphology: microscopically, the tumor showed small clusters and nests of infiltrative growth; a few areas showed tubules, and some eosinophilic secretions were observed in the lumen. (2) Immunohistochemistry and molecular genetics: Case 1 was partly positive for S-100, positive for SOX-10, and negative for ER, PR, and HER2 (2+). The result of HER2 gene amplification was negative. Breast and liver tissue lesions in Case 2 were positive for S-100 and SOX-10 but negative for ER and HER2. PR was positive in the liver lesions but showed moderate to strong expression in approximately 80% of the staining. Myoepithelial markers (p63 and calponin) showed loss of myoepithelium around the nests of invasive cancers. TP53 (R213Ter) showed somatic gene variations, and no exon amplification or deletion was detected in BRCA1/2. Conclusion. Invasive carcinoma originating from microadenosis has the same immunophenotype as microadenosis, and its prognosis is difficult to determine.
Open Access
a1-acid glycoprotein (AGP): a possible carrier of sialyl lewis X (slewis X) antigen in colorectal carcinoma
(Murcia : F. Hernández, 2005) Croce, M.V.; Sálice, V.C.; Lacunza, E.; Segal-Eiras, A.
Objectives: 1- to detect a1-acid glycoprotein (AGP) and sialyl Lewis x (sLex) in colorectal malignant, benign and normal samples; 2- to isolate AGP from colorectal cancer and 3- to study its immunoreactivity with an anti-sLex monoclonal antibody (MAb). Materials and methods: tissue and serum samples from 88 patients with colorectal cancer, 22 adenomas and 23 normal were included. Expression of AGP and sLex was studied by immunohistochemistry (IHC); isolation approach: AGP was precipitated with ammonium sulphate and immunoprecipitated with anti-AGP MAb. The immune complex formed was isolated by protein ASepharose CL-4B affinity chromatography and further eluted; fractions were analysed by SDS-PAGE and Western-blot. Statistical analysis was performed by means of Principal Component Analysis. Results: by Western blot employing anti-AGP MAb and sLex MAbs, isolated fractions from malignant samples showed a band at about 45kD. IHC revealed that AGP was expressed in 70% of colorectal carcinoma samples, 50% of benign and 35% of normals. SLex was detected in 31% of malignant samples, 41% of benign and in one normal sample. In malignant samples, AGP reaction comprised the whole specimen with a strong and homogeneous staining while normal and benign samples showed a restricted reaction. In cancer, sLex expression consisted in an intense reactivity in membrane, cellular debris and some cytoplasmic foci while normal and benign samples were occasionally stained. A statistically significant positive correlation was found between AGP and sLex expression. Serum AGP levels were measured by radial immunodiffusion and statistical comparative analysis with tissue expression did not show a correlation between both parameters. Conclusion: AGP may constitute a carrier of sLex in colorectal cancer.
Open Access
Aberrant PAX3 and PAX7 expression. A link to the metastatic potential of embryonal rhabdomyosarcoma and cutaneous malignant melanoma?
(Murcia : F. Hernández, 2003) Blake, J.; Ziman, M.R.
Transcription factors encoded by PAX3 and PAX7 are amongst the first expressed in the embryo, being principal regulators of neurogenic and myogenic progenitor cell specification and embryonic segmentation. The basis for this review lies in the supposition that genetic programs for cell migration, thought regulated by PAX3 and PAX7 during embryonic development, become tools used by the metastatic cell. In highly metastatic neoplasms arising from cells of neurogenic and myogenic lineages such as embryonal rhabdomyosarcoma and cutaneous malignant melanoma, markedly high expression levels of PAX3 and PAX7 support this supposition. As PAX3 and PAX7 are known to play a role in the regulation of migratory events in embryogenesis, it is possible that the metastatic potential of these tumours is directly linked to migratory properties conferred them through PAX expression. Here we provide a novel perspective by correlating metastasis with expression of PAX3, PAX7 and ephrin/Eph receptors as well as NCAMs, cell surface markers normally involved in migration and adhesion during development, and propose a role for PAX genes in the increased metastatic potential of these tumours.
Open Access
AHSA1 promotes the progression of lung cancer by enhancing the expression of HSP90α
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2026) Zifeng Jiang; Kun Gao; Min Wang; Biología Celular e Histología
Background. Lung cancer (LC) is a leading cause of malignancy-related morbidity and mortality worldwide. The activator of 90 kDa heat shock protein ATPase homolog 1 (AHSA1), one of the chaperones of heat shock protein 90 kDa (heat shock protein 90, HSP90), is involved in the maturation, stabilization, degradation, and function of oncogenic proteins. The aim of this study was to investigate the specific mechanism and role of AHSA1 in LC development. Methods. Expression of AHSA1 in LC was analyzed using The Cancer Genome Atlas (TCGA) database. AHSA1 expression in LC cells and tissues was assessed by qRT-PCR and western blotting. In addition, Kaplan-Meier plotter analysis and univariate and multivariate Cox analyses were used to evaluate the relationship between AHSA1 and clinicopathological variables and prognosis. The effects of AHSA1 on LC cell proliferation and migration were observed using cell counting kit-8, flow cytometry, wound healing, and Transwell assays. Target genes were predicted by bioinformatics and subsequently validated using a qRT-PCR assay. Results. AHSA1 exhibited significant upregulation in LC tissues and cell lines, with its elevated expression correlating with adverse prognostic outcomes in LC patients. Functional assays revealed that downregulation of AHSA1 markedly impedes the proliferation, migration, and invasion of LC cells. Conversely, overexpression of AHSA1 enhanced these malignant behaviors. Furthermore, bioinformatics analysis suggested a potential interaction between AHSA1 and HSP90α, which was also found to be highly expressed in LC cells, exhibiting a notable increase in expression levels following AHSA1 upregulation. Conclusions. AHSA1 is implicated in promoting the progression of LC by enhancing the malignant phenotype of cancer cells through the upregulation of HSP90α expression, which may underlie the association of AHSA1 expression with adverse clinicopathologic features in LC patients. These findings indicate that AHSA1 serves as a potential prognostic biomarker and represents a viable therapeutic target for LC
Open Access
Cancer progression and substance P
(F. Hernández y Juan F. Madrid. Universidad de Murcia. Departamento de Biología Celular e Histología, 2014) Coveñas, Rafael; Muñoz, Miguel
The substance P (SP)/neurokinin (NK)-1 receptor system plays an important role in cancer. After binding to the NK-1 receptor, SP induces tumor cell proliferation, migration of tumor cells (invasion, infiltration and metastasis) and angiogenesis. In contrast, NK-1 receptor antagonists inhibit tumor cell proliferation (tumor cells die by apoptosis), block the migratory activity of tumor cells, and exert antiangiogenic properties. The induction of apoptosis offers an appropriate method for cancer treatment. The NK-1 receptor can be considered as a target in cancer treatment. A common mechanism for cancer cell proliferation mediated by SP and the NK-1 receptor occurs and NK-1 receptor antagonists are broadspectrum antineoplastic drugs. The NK-1 receptor antagonist aprepitant is used in clinical practice and exerts an antitumor action against a large number of different human tumor cells. In the future, such antitumor action should be tested in human clinical trials.
Open Access
Cathepsin B may be a potential biomarker in cervical cancer
(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2012) Wu, Dan; Wang, Huijun; Li, Zhunan; Wang, Lihua; Zheng, Fengyun; Jiang, Juan; Gao, Yongtao; Zhong, Huifang; Huang, Yong; Suo, Zhenhe
Cathepsin B is a protease which is able to digest extracellular matrix. It is currently unknown whether cathepsin B plays a role in cervical cancer development and progression. With Q-PCR and Western blotting, we observed cathepsin B expression in cervical cancer cell line Hela cells. After the gene was silenced in HeLa cells with SiRNA, we confirmed that cathepsin B expressions at both mRNA and protein levels were significantly reduced. At the same time, cell proliferation, migration and invasion of the HeLa cells were significantly decreased compared to control cells. In addition, a significant regression of tumor growth in nude mice which received the siRNA targeted cathepsin B HeLa cells was observed. We further studied the expression of cathepsin B in a series of 169 clinical samples, including 56 invasive cervical squamous carcinoma, 85 CINs and 28 normal cervical tissues. It was found that cathepsin B expression in invasive carcinomas was significantly higher than that in the CINs and normal tissues (P<0.01). In addition, cathepsin B expression in the invasive carcinomas was positively correlated to tumor invasion depth and lymphatic metastasis. Our results indicate that cathepsin B may be a potential biomarker for further strategical clinical studies in cervical cancer
Open Access
Cathepsin K expression in melanoma is associated with metastases
(Universidad de Murcia. Departamento de Biología Celular e Histología, 2017) Petricevic, Slavica Juric; Pavlovic, Antonia; Capkun, Vesna; Becic, Kristijan; Durdov, Merica Glavina
Introduction. Melanoma of the skin shows a tendency to metastasize via lymph or blood secreting matrix metalloproteinases and cathepsins, which enable penetration through the dermis. Cathepsin K acts in cytoplasm of atypical melanocytes and completely cleaves internalized collagen. Materials and methods. Expression of cathepsin K was analyzed immunohistochemically in 45 melanomas and correlated to morphological and clinical parameters. Results. During six years follow up, 13 patients developed lymph node metastases and three of them distant metastases. Positive expression of cathepsin K was found in 19 cases. In univariate regression analysis histological type, pagetoid spread, mitotic activity and cathepsin K expression were significantly connected to metastases. Cathepsin K was significantly associated to histologic type, ulceration, pagetoid spread and mitotic rate. In multiple logistic regression adjusted to these variables, cathepsin K was an independent predictor in occurrence of metastases (P=0.015). Median to the occurrence of metastases was 40 months in patients with cathepsin K positive expression and 71 months in patients with cathepsin K negative expression (P<0.001). Conclusions. In this preliminary study positive expression of cathepsin K in melanoma of the skin is associated with other unfavorable prognostic factors. We consider cathepsin K expression in primary tumor would significantly precipitate occurrence of metastases.
Open Access
Circulating nucleic acids in plasma and serum (CNAPS) and its relation to stem cells and cancer metastasis: state of the issue
(Murcia : F. Hernández, 2004) García-Olmo, Dolores C.; Ruiz-Piqueras, R.
The presence of circulating cell-free nucleic acids has been demonstrated both in disease and health. In the last decade, a burst of papers about Circulating Nucleic Acids in Plasma and Serum (CNAPS) have been found in the literature, showing the scientific interest raised by this phenomenon and their putative clinical interest, especially in the field of cancer. Today, the detection of extracellular tumor-derived DNA and/or RNA is considered by many authors as a new molecular marker for situations such as cancer diagnosis, monitoring the outcome of a disease and, even, as a treatment response indicator. Furthermore, in some studies it has been suggested a possible role of tumor CNAPS in the development of metastasis. Specifically, the hypothesis known as the "genometastasis hypothesis" proposes that stem cells might be naturally transfected with dominant oncogenes as a result of dissemination of such genes in the plasma. On the other hand, current studies concerned with the biology of metastatic cells are increasingly being focused on the striking similarities found between these cells and stem cells. In this review we intend to expound and integrate two theories about metastatization: the "genometastasis hypothesis" and the idea of stem cells as cancer stem cells.
Open Access
Clinicopathological analysis of retroperitoneal solitary fibrous tumours: a study of 31 cases
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2022) Yuan, Xiaolu; Liu, Yuan; Wang, Xuming; Chen, Yu; Zhang, Lei
. A solitary fibrous tumour (SFT) is a mesenchymal tumour that exhibits fibroblast differentiation and rarely occurs in the retroperitoneum. The main purpose of this study was to explore the clinical manifestation, histopathological features and biological behaviour of retroperitoneal SFT. From 2011 to 2020, 31 patients were hospitalized and diagnosed with retroperitoneal SFTs. We summarized and analysed the morphological features, immunophenotype, treatment and prognosis. Patients (13 M; 18 F) ranged in age from 25 to 79 years with a mean age of 53.6 years. The main symptoms included an abdominal mass (48.4%) and abdominal discomfort (25.8%). The mean maximum diameter of the tumours was 12.9 cm (range, 4-40 cm). Histopathologically, there were 17 classic cases and 14 hemangiopericytoma-like cases. The tumour cells were positive for STAT6 (96.8%), CD34 (96.8%), CD99 (93.5%) and BCL-2 (90.3%). All patients were treated with complete surgical excision, and 3 of the patients also received chemotherapy. After a median follow up period of 44 months (range, 6 to 107 months), 2 patients died. Patients in the high- or intermediate-risk group were prone to metastasis and/or recurrence. The sites of metastases and/or recurrences involved the liver, bone and pelvis. The Ki-67 labelling index in the high-intermediate risk group (median, 10%) was significantly higher than that in the low-risk group (median, 3%). The retroperitoneal SFT demonstrates an indolent clinical course, and patients from the high- or intermediate-risk group require close follow-up. A Ki-67 labelling index ≥10% may be used as an important reference for prognosis.
Open Access
Clinicopathological features and lymph node metastatic patterns of gastric mixed adenoneuroendocrine carcinoma
(Universidad de Murcia. Departamento de Biología Celular e Histología, 2019) Chen, Hanrui; Shu, Man; Chen, Sile; Xue, Ling; Linn, Yua
Aims. Mixed adenoneuroendocrine carcinoma (MANEC), also known as high- grade mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN) in the World Health Organization (WHO) classification of tumors of the endocrine organs (2017), is a rare gastric malignancy. Here, we present 10 cases of gastric MANEC and analyse their clinicopathological features and lymph node metastatic patterns. Methods and results. Six patients were male, and four were female. The mean age of the patients was 67.9 years. Grossly, most tumors presented as ulcerative mass, located in gastric fundus or/and cardia. Microscopically, the neuroendocrine component, large cell neuroendocrine carcinoma in most cases (8/10), constituted 30-70% of the whole tumor. It was diffusely positive for CD56 or/and synaptophysin in all cases, but negative for chromogranin A in 9 cases. Ki-67 index was 50-80% in neuroendocrine component. The glandular component was moderately (6/10) or poorly (4/10) differentiated adenocarcinoma. Nine of 10 cases were positive for lymph node metastasis, with pure neuroendocrine component (6/9), or pure glandular component (1/9), or mixed components (2/9). The patients were treated with surgery, combining with chemotherapy (4/10), radiotherapy (2/10) and immunotherapy (1/10). Five patients died from tumor progress, with an average survival time of 18.6 months. The dead cases had predominant neuroendocrine component in primary tumor or in metastatic lymph nodes. Conclusions. Neuroendocrine component may determine the clinical behavior and outcome in gastric MANEC. Different metastatic component makes the selection of chemotherapy protocol more challenging.
Open Access
Crumbs3: Expression and biological significance in normal and neoplastic tissues
(2026) Akane Kitta-Kunihiro; Chiemi Ikude; Eisaku Kondo; Hidekazu Iioka; Biología Celular e Histología; Universidad de Murcia, Departamento de Biologia Celular e Histiologia
Cellular polarity plays a fundamental role in tissue organization and homeostasis, and its disruption is closely linked to tumorigenesis. Crumbs3 (CRB3), a conserved polarity protein, is essential for epithelial morphogenesis, tight-junction formation, and barrier function. This review summarizes current knowledge regarding CRB3 expression in normal and malignant human tissues and its dual roles in cancer progression. Systematic immunohistochemical analyses revealed strong CRB3 expression in non-neoplastic glandular epithelia of the gastrointestinal, hepato-pancreato-biliary, renal, and respiratory tracts, as well as in fetal tissues, suggesting its importance in organ development and maintenance. In neoplastic tissues, represented by colorectal adenocarcinoma and oral squamous cell carcinoma, CRB3 expression is preserved or even enhanced compared with normal tissues, which promotes tumor cell migration, triggering invasion/ metastasis as well as cellular proliferation through signaling pathways involving FGFR and RhoA activation. Conversely, previous studies reported that CRB3 functions as a tumor suppressor, based on findings that CRB3 expression induces loss of epithelial mesenchymal transition, whereas loss of CRB3 expression attenuates the integrity of tight junctions, resulting in significantly poorer prognosis in certain cancers. Current data thus suggest that the biological role of CRB3 in tumors is complex. Whether CRB3 acts as a tumor accelerator or suppressor may depend on the individual-specific, unique characteristics of tumor cells. Understanding these dual functions may contribute to the development of novel polarity-targeted therapeutic strategies for cancers of differing origin.
Open Access
Differential cellular localization of CELSR2 and ING4 and correlations with hormone receptor status in breast cancer
(Universidad de Murcia. Departamento de Biología Celular e Histología, 2018) Jiang, Liejun; Zhang, Xiliu; Xiang, Chenglin; Geradts, Joseph; Wei, Qiang; Liang, Yuanzi; Huang, Huayi; Xu, Jun Fa
CELSR2 is postulated to be a receptor involved in contact-mediated communication; however, its expression and function in cancer remain unknown. ING4 is a tumor suppresor encoded by the ING4 gene which inhibits cell growth. The expression of CELSR2 and ING4 in breast tumors and in benign epithelial cells have been analyzed and correlated with HER2, ER, and PR status. Immunohistochemistry was used to analyze the expression of CELSR2 and ING4 protein in breast tumors and benign epithelial cells. The differential cellular localization of both markers was analyzed and results were also correlated with HER2, ER, and PR status. CELSR2 and ING4 cytoplasmic expression was significantly stronger in tumors than in benign epithelial cells, while the nuclear expression of both markers was significantly stronger in benign epithelial cells than in tumors. When comparing the two markers in the same type of tissues, the nuclear expression of CELSR2 was significantly stronger than cytoplasmic in benign epithelial cells, while there was no significant difference in the cellular localization of CELSR2 in tumors. For ING4, the cytoplasmic expression was significantly stronger than nuclear expression in tumors, while in benign epithelial cells, ING4 was expressed at similar levels in both compartments. There was no correlation between CELSR2 expression and HER2, ER, and PR status in tumors. However, the cytoplasmic expression of ING4 was associated with HER2 positivity in tumors. Both CELSR2 and ING4 display increased cytoplasmic staining in breast cancer cells compared to benign epithelium, suggesting a possible role of both genes in the pathogenesis of human mammary neoplasia.
Open Access
Emerging role of fatty acid binding proteins in cancer pathogenesis
(Universidad de Murcia. Departamento de Biología Celular e Histología, 2019) Gurung, Shilpa; Po Sin Chung, Katherine; Lee, Terence Kin Wah
Fatty acid binding proteins (FABPs) are 15- kDa proteins responsible for the transport of fatty acids both intracellularly and extracellularly. Consisting of 12 different isoforms, some of the proteins have been found to be released in the serum and to be correlated with various diseases including cancer. Differential expression of these proteins has been reported to result in cancer pathogenesis by modulating various cancer signaling pathways; hence, in this review, we present the recent studies that have investigated the roles of different kinds of FABPs in different types of cancer and any possible underlying mechanisms to better understand the role of FABPs in cancer progression.
Open Access
Expression of CXCR4 and MMP-2 is associated with poor prognosis in patients with osteosarcoma
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2020) Gong, Chen; Sun, Kai; Xiong, Hui-hua; Sneh, Tal; Zhang, Jing; Zhou, Xiao; Yan, Peng; Wang, Jian-hua
Backgroud. Osteosarcoma is a primary malignant tumor with a high tendency to form metastasis and poor prognosis. Consequently, finding effective early indicators of metastases is crucial for identifying and treating high-risk patients. CXCR4 and MMP-2 have been found to strongly correlate with invasion and metastasis of malignant tumors, including osteosarcoma. Materials and Methods. Our study evaluated CXCR4 in conjunction with MMP-2 as an important clinicopathological prognostic predictor for metastasis and overall survival of osteosarcoma. 73 patients’ clinical data and pathological samples were retrieved for the study. A median time of 36 months follow-up was performed to evaluate for tumor metastasis and patient survival. CXCR4 and MMP-2 proteins in tumor tissues were detected by immunohistochemistry on paraffin- embedded tissue sections. Results. The positive expression rate of CXCR4 and MMP-2 was 68.5% and 54.8% respectively, and of the 45 patients who developed distal metastasis, 33 and 28 patients had positive expression of CXCR4 and MMP-2 respectively. The median metastasis-free survival was 72.00 months in the CXCR4-negative group and 14.00 months in the CXCR4 positive group. Furthermore, median overall survival was 73.77 and 24.00 months in these same two groups. Further, the median metastasis-free survival was 66.51 months in the MMP-2 negative group and 9.00 months in the MMP-2 positive group. The median overall survival was 75.07 and 19.00 months in these same two groups. MMP2 and metastasis remained the significant and independent prognostic factors for metastasis-free survival and overall survival by using the COX regression model adjusted for the multivariate predictors of survival. Conclusion. Our results suggest that metastasis and MMP-2 are both independent prognostic indicators for metastasis-free and overall survival of osteosarcoma patients.
Open Access
Expression of glucose-regulated protein 78 as prognostic biomarker for triple-negative breast cancer
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2020) Yang, Chenlian; Zhang, Zhiwei; Zou, Yutian; Gao, Guanfeng; Liu, Lingrui; Xu, Haifan; Liu, Feng
Introduction. glucose-regulated protein78 (GRP78) is a stress - induced endoplasmic reticulum chaperone protein. It is closely related to the occurrence, development, proliferation, differentiation and drug resistance of breast cancer. However, the association and clinicopathological features between GRP78 and triple negative breast cancer (TNBC) remain to be studied. Material and Methods. Clinical and pathological characteristics and overall survival were analysed retrospectively in 179 surgically resected TNBC patients. GRP78 was detected by immunohistochemistry (IHC) using breast cancer tissue microarrays (TMAs), and the association between GRP78 levels and clinicopathological factors and prognosis was analyzed. Furthermore, GRP78 expression in human TNBC and NTNBC cell lines was detected by Western blot and qRT-PCR. After Si-GRP78 knocked-down GRP78 in MDA-MB-231 and BT549 cell lines, cell proliferation was detected using Cell Counting Kit-8 (CCK-8) and cell colony formation was detected by crystal violet staining, respectively. Results. GRP78 was expressed in triple negative breast cancer (TNBC). GRP78 expression was significantly associated with invasive, distant metastasis and proliferation of TNBC (P<0.05). In addition, patients with positive GRP78 expression had shorter overall survival (OS) and disease-free survival (DFS). And the high expression of GRP78 was significantly associated with disease-free survival (DFS) in patients with TNBC (P<0.001). Conclusions. These findings improve our understanding of the expression pattern of GRP78 in TNBC and clarify the role of GRP78 as a promising prognostic biomarker for triple-negative breast cancer.
Open Access
Expression of proliferation marker Ki67 correlates to occurrence of metastasis and prognosis, histological subtypes and HPV DNA detection in penile carcinomas
(Murcia : F. Hernández, 2007) Protzel, C.; Knoedel, J.; Zimmermann, U.; Woenckhaus, C.; Poetsch, M.; Giebel, J.
Clinical outcome of penile squamous cell carcinoma (PSCC) largely depends on the presence of lymph node metastasis. In search of a valuable marker predicting the risk for metastasis, the expression of Ki67 was investigated immunohistochemically in primary tumors and compared to presence of inguinal lymph node metastasis. As human papilloma virus (HPV) is thought to affect Ki67 expression, we evaluated whether occurrence of HPV DNA correlates to Ki67 score or metastatic potential. Samples originated from patients subjected to resection of invasive SCC of penis. Immunohistochemistry was done on paraffin-embedded sections using a monoclonal antibody against Ki67. After DNA isolation from paraffin embedded tissue the presence of HPV 6/11, HPV 16 and HPV 18 DNA was analyzed by PCR. Statistical analysis was done using two tail unpaired t test and Chi-square test. Four of 28 patients showed a weak Ki67 expression, without displaying lymph node metastasis. Among 17 patients showing an intermediate Ki67 index, eight exhibited metastases while in all seven patients with a strong expression of Ki67 lymph node metastases were found. The median Ki67 expression in metastastic lesions was significantly different (50.3%) from tumors without lymph node metastasis (31.8%) (p=0.024). Furthermore, a correlation between presence of HPV DNA and strong Ki67 expression was determined (p=0.009). Since our study demonstrated a strong Ki67 labeling index significantly associated to positive lymph nodes, we suggest Ki67 expression as a prognostic marker for lymph node metastasis in penile squamous carcinoma.
Open Access
Expression, function and clinical relevance of MIA (Melanoma Inhibitory Activity)
(Murcia : F. Hernández, 2002) Bosserhoff, A.K.; Buettner, R.
Despite its ambiguous name the protein melanoma-inhibitory-activity (MIA) was identified as a key molecule involved in progression and metastasis of malignant melanomas. Therefore, in this review we intend to update the current knowledge on expression patterns, transcriptional regulation, function and clinical relevance of MIA. Furthermore, we will cover the recently discovered MIA homologous proteins OTOR/MIAL, MIA 2 and TANGO. In order to identify autocrine growth-regulatory factors secreted by melanoma cells, MIA was purified and cloned. Subsequent analyses of non-neoplastic tissues revealed specific MIA expression patterns in cartilage. In neoplastic tissues MIA expression was detected in malignant melanomas, in chondrosarcomas and less frequently in a variety of diff e r e n t adenocarcinomas including breast and colon cancers. For melanoma cells and chondrocytes it was shown that regulation of expression pattern was controlled on the level of mRNA transcription by defined transcription factors. Evidence obtained from in vitro and in vivo experiments indicated that MIA plays an important functional role in melanoma metastasis and invasion. A number of studies from different laboratories evaluated MIA as a highly specific and sensitive marker, clinically useful for follow-up and therapy-monitoring of patients with malignant melanomas. In addition, preliminary data suggests a further potential application as a surrogate marker for measuring cartilage damage in rheumatoid arthritis. Recently, it has become evident that MIA belongs to a gene family of four homologous proteins, MIA, OTOR (FDP, MIAL), MIA 2 and TANGO. Determination of the three-dimensional structure in solution identified MIA as the first member of this novel family of secreted, extracellular proteins adopting an SH3 domain-like fold. The data suggest specific protein-protein interactions with components of the extracellular matrix and possibly
Open Access
Gelatinases and their inhibitors in tumor metastasis: from biological research to medical applications
(Murcia : F. Hernández, 2002) Giannelli, G.; Antonaci, S.
The involvement of matrix metalloproteinase (MMPs)-2 and -9, also known as gelatinases, in cancer cell migration and invasion has been well documented, although it is not yet clear how they facilitate metastasis formation in the course of malignancies. The idea that gelatinases are responsible for degradation of extracellular matrix (ECM) components and breakdown of basement membrane (BM) tissue boundaries has turned out not to be entirely correct. An action by remodelling the ECM components of the BM exposing new cryptic sites, or releasing growth factors, cytokines, or active ECM proteolysed fragments seems to be nearer to the truth. On the other hand, tissue inhibitors of gelatinase activity (TIMP-2), are involved both in the MMP-2 activation process, in concert with membrane type 1-MMP (MT1-MMP), and in the inhibition of gelatinolytic activity. Therefore proteolysis, the central step for cancer metastasis, should occur as a result of an imbalance between MMP-2 and TIMP-2. Many studies have reported the importance of this balance in patients with different malignancies, and considerable effort is currently being spent on the study of molecules that can shift the balance in favour of inhibition of MMP proteolytic activity. In this review we focus on the role of gelatinase activity in cancer invasion, addressing the following issues: how and where proteolysis occurs in cancer tissues, how it can be regulated, what the clinical implications are of the studies reported in literature so far, and finally what the future developments in this field that could have an impact on the management of patients affected by malignancies may be.
Open Access
Gene products involved in metastasis of bladder cancer
(Murcia : F. Hernández, 2003) Davies, B.R.
Metastasis is usually responsible for mortality in patients suffering from muscle invasive bladder cancer. Whilst expression of a great number of genes and their protein products have been associated with metastasis and/or poor prognosis in bladder cancer, evidence that they actively drive the metastatic process, and hence make potentially good therapeutic targets, is often lacking. This is due to the limited number and application of effective animal models which reflect the pathogenesis of the human disease. In this review I will discuss the processes involved in metastasis, consider the established animal models of bladder cancer progression and metastasis, and review the evidence for a role of various gene products in this process. Consideration of clinical studies in conjunction with evidence from experimental animal models reveals that the tyrosine kinase receptor erbB1/EGFR, the calcium binding protein S100A4 and the the cell cycle arrest/apoptosis-inducing p53 protein are amongst the most promising targets for therapy against metastatic disease in patients with bladder cancer.
Open Access
Growth factors in mechanisms of malignancy: roles for TGF-í3 and FGF
(Murcia : F. Hernández, 1996) Wright, J.A.; Huang, A.
Malignant progression is a complex process involving the accumulation of multiple genetic alterations leading to changes in many specialized cell functions. Important in this process is the loss of growth control which is frequently associated with modifications in growth factor production, and growth factor response pathways. Indeed, oncogenes have been characterized that code for polypeptide growth factors or their receptors, and many tumor cell populations release potently mitogenic growth factors which contribute to the malignant properties of tumor cells. In this review, the importance of growth factors in mechanisms of malignant progression is emphasized, using as examples the transforming growth factor-beta (TGF-6) and fibroblast growth factor (FGF) families. We describe many of the properties and biological activities of these two families of growth factors, focusing on mechanisms of autocrine and intracrine mitogenic stimulation of tumor cell proliferation and malignant progression. The discussion includes evidence for altered growth factor expression in tumor cells, and the relationship between these changes in growth factors and alterations in the regulation of DNA synthesis, cell proliferation, protease production and cell motility required for invasion and metastasis. Recent studies are described that show that aberrant expression of TGF-BI, bFGF or K-FGF results in dramatic changes in the genetic stability of cells, leading to increased rates of spontaneous gene amplification and the generation of drug resistant variants. These findings describe new malignancy relevant functions for altered growth factor expression.