Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0677930 (primary tumor)
 20,210 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The interaction between tumor cells and the microenvironment has substantial effects on tumor cell behavior by influencing cell-cell as well as cell-matrix contacts. The underlying molecular mechanisms are only partially unraveled. In this review we focus on the influence of the stromal microenvironment, especially collagen type I and type III on cellular adhesion and epithelial to mesenchymal transition (EMT). Extensive studies have emphasized that components of the microenvironment such as fibrillar collagen or growth factors like transforming growth factor beta are involved in induction of dedifferentiation of epithelial cells accompanied by disruption of the E-cadherin adhesion complex and reduced E-cadherin concentrations. On the molecular level many different proteins have been identified which are involved in the regulation of EMT, such as activation of integrins, intracellular kinases such as Src, focal adhesion kinase (FAK) or phosphatidylinositol-3 kinase (PI3-kinase) and alteration of catenin phosphorylation. The reduced cellular adhesion influences the tissue integrity and allows tumor cells to disseminate from the primary tumor representing an early step in cancer metastasis.
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PMID:Microenvironmental regulation of E-cadherin-mediated adherens junctions. 1850 91

Signet-ring adenocarcinoma is an aggressive form of primary bladder adenocarcinoma that has been associated with poor outcomes. The utility of immunohistochemical markers in tumors with signet-ring morphology may vary from more typical adenocarcinomas arising at the same location, although this has not been examined in bladder adenocarcinoma. We examined a series of bladder adenocarcinomas to determine the impact of signet-ring cell features on clinical outcomes and immunohistochemical findings. We identified 25 patients with bladder adenocarcinoma, ranging in age from 28 to 78 years (mean, 57 years) and with a male-female ratio of 18:7. Six cases were urachal in origin. Signet-ring cells occurred in 19 of 25 bladder adenocarcinomas (76%) and ranged from 5% to 100% of tumor volume, with most tumors demonstrating more than 60% signet-ring cell differentiation (15/19), when present. Regional lymph node metastases were present in 8 of 19 patients (42%) who underwent cystectomy. The percentage of tumor containing signet-ring cells was significantly associated with the presence of adverse pathologic features (defined as unresectable primary tumor or regional lymph node metastasis, P = .013) and decreased overall survival (P = .034), and the latter remained significant in multivariable analysis after adjusting for positive soft tissue margins (P = .026). A comparison between immunohistochemical markers frequently used to analyze bladder adenocarcinoma demonstrated decreased expression of several markers in signet-ring (n = 9) versus colonic-type (n = 8) morphology, including CDX-2, beta-catenin, and E-cadherin, although these results did not reach statistical significance. In summary, the extent of signet-ring differentiation in bladder adenocarcinoma is associated with worsened survival and higher stage disease; the utility of immunohistochemical analysis in foci consisting of predominant signet-ring cells may be limited, although further studies that address this finding are needed.
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PMID:Clinicopathologic features and utility of immunohistochemical markers in signet-ring cell adenocarcinoma of the bladder. 1878 86

To date, the most effective cure for metastatic melanoma remains the surgical resection of the primary tumor. Recently, tocotrienol-rich-fraction has shown antiproliferative effect on cancer cells. To elucidate this anticancer property in malignant melanoma, this study aimed, first, to identify the most potent isomer for eliminating melanoma cells and second to decipher the molecular pathway responsible for its activity. Results showed that the inhibitory effect of gamma-tocotrienol was most potent, which resulted in induction of apoptosis as evidenced by activation of procaspases and the accumulation of sub-G1 cell population. Examination of the prosurvival genes revealed that the gamma-tocotrienol-induced cell death was associated with suppression of NF-kappaB, EGF-R, and Id family proteins. Meanwhile, gamma-tocotrienol treatment also resulted in induction of JNK signaling pathway, and inhibition of JNK activity by selective inhibitor was able to partially block the effect of gamma-tocotrienol. Interestingly, gamma-tocotrienol treatment led to suppression of mesenchymal markers and the restoration of E-cadherin and gamma-catenin expression, which was associated with suppression of cell invasion capability. Furthermore, synergistic effect was observed when cells were cotreated with gamma-tocotrienol and chemotherapy drugs. Together, our results demonstrated for the first time the anti-invasion and chemonsensitization effect of gamma-tocotrienol against human malignant melanoma cells.
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PMID:Evidence of gamma-tocotrienol as an apoptosis-inducing, invasion-suppressing, and chemotherapy drug-sensitizing agent in human melanoma cells. 1937 9

The purpose of this study was to investigate invasion- and metastasis-related genes in gastric cancer. To this end, we used the transwell system to select a highly invasive subcell line from minimally invasive parent cells and compared gene expression in paired cell lines with high- and low-invasive potentials. Lysyl oxidase-like 2 (LOXL2) was overexpressed in the highly invasive subcell line. Immunohistochemical analysis revealed that LOXL2 expression was markedly increased in carcinoma relative to normal epithelia, and this overexpression in primary tumor was significantly associated with depth of tumor invasion, lymph node metastasis and poorer overall survival. Moreover, LOXL2 expression was further increased in lymph node metastases compared with primary cancer tissues. RNA interference-mediated knockdown and ectopic expression of LOXL2 showed that LOXL2 promoted tumor cell invasion in vitro and increased gastric carcinoma metastasis in vivo. Subsequent mechanistic studies showed that LOXL2 could activate both the Snail/E-cadherin and Src kinase/Focal adhesion kinase (Src/FAK) pathways. However, secreted LOXL2 induced gastric tumor cell invasion and metastasis exclusively via the Src/FAK pathway. Expression correlation analysis in gastric carcinoma tissues also revealed that LOXL2 promoted invasion via the Src/FAK pathway but not the Snail/E-cadherin pathway. We then evaluated secreted LOXL2 as a target for gastric carcinoma treatment and found that an antibody against LOXL2 significantly inhibited tumor growth and metastasis. Overall, our data revealed that LOXL2 overexpression, a frequent event in gastric carcinoma progression, contributes to tumor cell invasion and metastasis, and LOXL2 may be a therapeutic target for preventing and treating metastases.
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PMID:Secreted LOXL2 is a novel therapeutic target that promotes gastric cancer metastasis via the Src/FAK pathway. 1962 48

The role of polarity signaling in cancer metastasis is ill defined. Using two three-dimensional culture models of mammary epithelial cells and an orthotopic mouse model of breast cancer, we reveal that Par6 signaling, which is regulated directly by TGFbeta, plays a role in breast cancer metastasis. Interference with Par6 signaling blocked TGFbeta-dependent loss of polarity in acini-like structures formed by non-transformed mammary cells grown in three-dimensional structures and suppressed the protrusive morphology of mesenchymal-like invasive mammary tumor cells without rescuing E-cadherin expression. Moreover, blockade of Par6 signaling in an in vivo orthotopic model of metastatic breast cancer induced the formation of ZO-1-positive epithelium-like structures in the primary tumor and suppressed metastasis to the lungs. Analysis of the pathway in tissue microarrays of human breast tumors further revealed that Par6 activation correlated with markers of the basal carcinoma subtype in BRCA1-associated tumors. These studies thus reveal a key role for polarity signaling and the control of morphologic transformation in breast cancer metastasis.
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PMID:A role for the TGFbeta-Par6 polarity pathway in breast cancer progression. 1966 98

Different p120ctn isoforms exert different, even opposing, effects on tumor cell growth depending on the level of E-cadherin expression, but the impact on clinicopathological parameters of lung cancer patients is not clear. Herein, we investigate the correlation between pan-p120ctn, p120ctn isoform 1, and E-cadherin expression and clinicopathological parameters, especially prognosis, of lung cancer patients. Immunohistochemistry on 20 specimens of normal bronchial epthelium revealed that, p120ctn isoform 1 was not expressed at the membrane; only weak cytoplasmic expression was seen. In contrast, both pan-p120ctn and E-cadherin were expressed clearly on the cell membrane or in the cytoplasmic peri-membrane region. However, in squamous cell lung cancer or lung adenocarcinomas, p120ctn isoform 1 over-expressed in the cytoplasm accompany with the abnormal pan-p120ctn and E-cadherin cytoplasm expression. p120ctn isoform 1 over-expression correlated positively with lymph node metastasis, poor differentiation, histological type, and high TNM stage. Cytoplasmic p120ctn isoform 1 expression in metastatic nodules was always higher than in the primary tumor. While the mean survival times of patients with normal p120 ctn isoform 1 or pan-p120ctn expression differed significantly, the mean survival times of patients with abnormal expression were similar. Lymph node metastasis, TNM stage, abnormal pan-p120ctn expression, and p120ctn isoform 1 over-expression were all independent factors affecting the prognosis of lung cancer patients. Over-expression of p120ctn isoform 1 positively correlated with poor prognosis of lung cancer patients, and therefore may be a useful marker of lung cancer patient survival.
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PMID:p120ctn isoform 1 expression significantly correlates with abnormal expression of E-cadherin and poor survival of lung cancer patients. 1976 14

A 57-year-old woman, with left choroidal melanoma treated by laser photocoagulation and a history of repeated vitrectomies, checked for left eye acute pain and foreign body-like sensation, symptoms that occurred after three years since the primary tumor treatment. The left eyeball was enucleated and the tissues were investigated by immunohistochemistry for markers associated with cell differentiation, proliferation and adhesion, cell cycle regulation, apoptosis control, vascularization, invasiveness and local immune response. We identified, in fact, two independent tumors, with different localization and sharing some common features, markers of a highly aggressive potential: loss of cell differentiation markers and cell cycle regulators, ability to avoid death by suppressing Fas antigen expression and important invasive capacity by down regulation of E-cadherin expression. However, only in the posterior tumor, we found cells with high proliferation rate, Fas ligand molecule expression and MMP-9 secretion, acquisitions associated with a much more aggressive behavior. These particular phenotypes allowed the posterior cells to grow and to invade the surrounding tissues more rapidly than the anterior ones, leading to the development of a large size tumoral mass, responsible for the clinical symptoms. Photocoagulation, by destroying the tissues, makes impossible the evaluation of the primary tumor's biological features, important for the tumor evolution. The absence of these data stresses the importance of patient monitoring, eventually addressing a panel of soluble markers associated with recurrence or metastasis development.
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PMID:A rare case of double recurrent choroidal melanoma, with distinctive immunohistochemical features. 2019 Nov 42

The proteins involved in breast cancer initiation and progression are still largely elusive. To gain insights into these processes, we conducted quantitative proteomic analyses with 21T series of breast cell lines, which include a normal, primary tumor and a metastatic tumor that were isolated from a single patient. Stable isotope labeling of amino acid in cell culture followed by LC-MS/MS analysis was performed and deregulated proteins were identified using statistical analysis. Gene ontology analysis revealed that proteins involved in metabolic processes were the most deregulated in both tumorigenesis and metastasis. Interaction network analysis indicated that ERBB2 signaling played a critical role in tumorigenesis. In addition to known markers such as ERBB2 and E-cadherin, novel markers, including BRP44L, MTHFD2 and TIMM17A, were found to be overexpressed in 21T breast cancer cells and verified in additional breast cell lines. mRNA expression analysis as well as immunohistochemistry analysis in breast cancer tissues indicated that expression level of TIMM17A was directly correlated with tumor progression, and survival analysis suggested that TIMM17A was a powerful prognosis factor in breast cancer. More interestingly, overexpression and siRNA knockdown experiments indicated an oncogenic activity of TIMM17A in breast cancer. Our study provides a list of potential novel markers for breast cancer tumorigenesis and metastasis using a unique cell model. Further studies on TIMM17A as well as other markers on the list may reveal mechanisms that result in more effective therapeutics for cancer treatment.
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PMID:Quantitative proteomics study of breast cancer cell lines isolated from a single patient: discovery of TIMM17A as a marker for breast cancer. 2019 62

We report the case of a common type papillary thyroid carcinoma (PTC) patient who developed early recurrence and persistent disease even after ablation therapy. The patient was an 80-year-old man that was incidentally found to have a mass lesion in the left lower lobe of his thyroid. A total thyroidectomy and a left side modified radical neck dissection were performed; histological examination revealed a common type PTC. The patient underwent lymph node dissection twice for recurrence and (131)I-Na ablations for fluctuated elevation of serum thyroglobulin. The resected tumor and recurrence in lymph nodes revealed non-solid type papillary carcinoma with mixed features of less well-differentiated morphology, which we suggest included loss of cellular polarity/cohesiveness, tall cells and columnar cells. Immunohistochemistry revealed high a MIB-1 labeling index (15-20%) in both the primary tumor and the metastatic tumor in the lymph nodes. p53 immunoreaction was found positive at very low level (<5%). E-cadherin was faintly positive in a few cells of the primary tumor and negative in the metastatic site. We recently proposed a new classification for follicular cell tumors of the thyroid gland, and this case is an example of moderately-differentiated adenocarcinoma according to our classification.
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PMID:Non-solid type thyroid carcinoma: a case report of moderately differentiated adenocarcinoma of the thyroid. 2059 75

GlcNAcylation, a dynamic posttranslational modification, is involved in a wide range of biological processes and some human diseases. Although there is emerging evidence that some tumor-associated proteins are modified by GlcNAcylation, the role of GlcNAcylation in tumor progression remains unclear. Here, we show that GlcNAcylation enhances the migration/invasion of breast cancer cells in vitro and lung metastasis in vivo. The decrease of cell surface E-cadherin is the molecular mechanism underlying GlcNAcylation-induced breast cancer metastasis. p120 and beta-catenin, but not E-cadherin, are GlcNAcylated; the GlcNAcylation of p120 and beta-catenin might play roles in the decrease of cell surface E-cadherin. Moreover, immunohistochemistry analysis indicated that the global GlcNAcylation level in breast tumor tissues is elevated significantly as compared with that in the corresponding adjacent tissues; further, GlcNAcylation was significantly enhanced in metastatic lymph nodes compared with their corresponding primary tumor tissues. This is the first report to clearly elucidate the roles and mechanisms whereby GlcNAcylation influences the malignant properties of breast cancer cells. These results also suggest that GlcNAcylation might be a potential target for the diagnosis and therapy of breast cancer.
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PMID:GlcNAcylation plays an essential role in breast cancer metastasis. 2061 Jun 29


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