scholarly journals Unveiling a Hidden Biomarker of Inflammation and Tumor Progression: The 65 kDa Isoform of MMP-9 New Horizons for Therapy

2021 ◽  
Vol 44 (1) ◽  
pp. 105-116
Author(s):  
Rocco Rossano ◽  
Marilena Larocca ◽  
Margherita Macellaro ◽  
Domenico Bilancia ◽  
Paolo Riccio
Keyword(s):  
Breast Cancer ◽  
Tumor Progression ◽  
Cancer Metastasis ◽  
Active Form ◽  
Pathological Process ◽  
The Other ◽  
New Horizons ◽  
Suitable Marker ◽  
Metalloproteinase 9 ◽  
Very High

Cancer metastasis is a stage of the disease where therapy is mostly ineffective; hence, the need to find reliable markers of its onset. The metalloproteinase-9 (MMP-9, gelatinase B) in its 82 kDa active form, is a good candidate, but here we show that the correspondent little known 65 kDa active MMP-9 isoform, often misrepresented with the other gelatinase MMP-2, is a more suitable marker. Sera from patients with lung and breast cancer were analyzed by bidimensional zymography to detect the activity of MMP-9 and MMP-2. Enzyme identity was confirmed by comparison with MMP-9 standards and by western blotting. The 65 kDa isoform of MMP-9 is a suitable biomarker to monitor tumor progression from tissue neoplasms to metastatic stage, as its activity begins to appear when disease severity increases and becomes very high in metastasis. Moreover, the 65 kDa MMP-9, which derives from the 82 kDa MMP-9, no longer responds to natural MMP-9 inhibitors. As its activity cannot be controlled, its appearance may warn that the pathological process is becoming irreversible. Identification and inhibition of the enzymes converting the inhibitor-sensitive 82 kDa MMP-9 into the corresponding “wild” 65 kDa MMP-9 may allow to develop therapies capable of blocking metastases.

scholarly journals Biological Functions of the Genes in the Mammaprint Breast Cancer Profile Reflect the Hallmarks of Cancer

2010 ◽  
Vol 5 ◽  
pp. BMI.S6184 ◽  
Author(s):  
Sun Tian ◽  
Paul Roepman ◽  
Laura J van't Veer ◽  
Rene Bernards ◽  
Femke De Snoo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Progression ◽  
Molecular Mechanisms ◽  
Cancer Metastasis ◽  
Biological Activities ◽  
Tumor Biology ◽  
Molecular Signature ◽  
Biological Functions ◽  
Hallmarks Of Cancer ◽  
Network Analyses

Background MammaPrint was developed as a diagnostic tool to predict risk of breast cancer metastasis using the expression of 70 genes. To better understand the tumor biology assessed by MammaPrint, we interpreted the biological functions of the 70-genes and showed how the genes reflect the six hallmarks of cancer as defined by Hanahan and Weinberg. Results We used a bottom-up system biology approach to elucidate how the cellular processes reflected by the 70-genes work together to regulate tumor activities and progression. The biological functions of the genes were analyzed using literature research and several bioinformatics tools. Protein-protein interaction network analyses indicated that the 70-genes form highly interconnected networks and that their expression levels are regulated by key tumorigenesis related genes such as TP53, RB1, MYC, JUN and CDKN2A. The biological functions of the genes could be associated with the essential steps necessary for tumor progression and metastasis, and cover the six well-defined hallmarks of cancer, reflecting the acquired malignant characteristics of a cancer cell along with tumor progression and metastasis-related biological activities. Conclusion Genes in the MammaPrint gene signature comprehensively measure the six hallmarks of cancer-related biology. This finding establishes a link between a molecular signature and the underlying molecular mechanisms of tumor cell progression and metastasis.

scholarly journals Heparan Sulfate and Heparanase as Modulators of Breast Cancer Progression

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
Angélica M. Gomes ◽  
Mariana P. Stelling ◽  
Mauro S. G. Pavão
Keyword(s):  
Breast Cancer ◽  
Heparan Sulfate ◽  
Tumor Progression ◽  
Cancer Progression ◽  
Cancer Metastasis ◽  
Antitumor Agents ◽  
Breast Cancer Metastasis ◽  
Tumor Type ◽  
Matrix Assembly ◽  
Genetic Components

Breast cancer is defined as a cancer originating in tissues of the breast, frequently in ducts and lobules. During the last 30 years, studies to understand the biology and to treat breast tumor improved patients’ survival rates. These studies have focused on genetic components involved in tumor progression and on tumor microenvironment. Heparan sulfate proteoglycans (HSPGs) are involved in cell signaling, adhesion, extracellular matrix assembly, and growth factors storage. As a central molecule, HSPG regulates cell behavior and tumor progression. HS accompanied by its glycosaminoglycan counterparts regulates tissue homeostasis and cancer development. These molecules present opposite effects according to tumor type or cancer model. Studies in this area may contribute to unveil glycosaminoglycan activities on cell dynamics during breast cancer exploring these polysaccharides as antitumor agents. Heparanase is a potent tumor modulator due to its protumorigenic, proangiogenic, and prometastatic activities. Several lines of evidence indicate that heparanase is upregulated in all human sarcomas and carcinomas. Heparanase seems to be related to several aspects regulating the potential of breast cancer metastasis. Due to its multiple roles, heparanase is seen as a target in cancer treatment. We will describe recent findings on the function of HSPGs and heparanase in breast cancer behavior and progression.

scholarly journals Very High Frequency of Hypermethylated Genes in Breast Cancer Metastasis to the Bone, Brain, and Lung

2004 ◽  
Vol 10 (9) ◽  
pp. 3104-3109 ◽  
Author(s):  
Jyoti Mehrotra ◽  
Mustafa Vali ◽  
Megan McVeigh ◽  
Scott L. Kominsky ◽  
Mary Jo Fackler ◽  
...  
Keyword(s):  
Breast Cancer ◽  
High Frequency ◽  
Cancer Metastasis ◽  
Breast Cancer Metastasis ◽  
Very High Frequency ◽  
Very High ◽  
Hypermethylated Genes

scholarly journals Overexpression of Lrp5 enhanced the anti-breast cancer effects of osteocytes in bone

Bone Research ◽  
2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Shengzhi Liu ◽  
Di Wu ◽  
Xun Sun ◽  
Yao Fan ◽  
Rongrong Zha ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Wnt Signaling ◽  
Tumor Progression ◽  
Tumor Cells ◽  
Cancer Metastasis ◽  
Animal Experiments ◽  
Breast Cancer Metastasis ◽  
Conditional Knockout ◽  
Knockout Mouse Model ◽  
Cell Based Therapy

AbstractOsteocytes are the most abundant cells in bone, which is a frequent site of breast cancer metastasis. Here, we focused on Wnt signaling and evaluated tumor-osteocyte interactions. In animal experiments, mammary tumor cells were inoculated into the mammary fat pad and tibia. The role of Lrp5-mediated Wnt signaling was examined by overexpressing and silencing Lrp5 in osteocytes and establishing a conditional knockout mouse model. The results revealed that administration of osteocytes or their conditioned medium (CM) inhibited tumor progression and osteolysis. Osteocytes overexpressing Lrp5 or β-catenin displayed strikingly elevated tumor-suppressive activity, accompanied by downregulation of tumor-promoting chemokines and upregulation of apoptosis-inducing and tumor-suppressing proteins such as p53. The antitumor effect was also observed with osteocyte-derived CM that was pretreated with a Wnt-activating compound. Notably, silencing Lrp5 in tumors inhibited tumor progression, while silencing Lrp5 in osteocytes in conditional knockout mice promoted tumor progression. Osteocytes exhibited elevated Lrp5 expression in response to tumor cells, implying that osteocytes protect bone through canonical Wnt signaling. Thus, our results suggest that the Lrp5/β-catenin axis activates tumor-promoting signaling in tumor cells but tumor-suppressive signaling in osteocytes. We envision that osteocytes with Wnt activation potentially offer a novel cell-based therapy for breast cancer and osteolytic bone metastasis.

scholarly journals Aspects of the Epigenetic Regulation of EMT Related to Cancer Metastasis

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3435
Author(s):  
Ewa Nowak ◽  
Ilona Bednarek
Keyword(s):  
Gene Expression ◽  
Cancer Metastasis ◽  
Epithelial To Mesenchymal Transition ◽  
Cpg Islands ◽  
Pathological Process ◽  
The Other ◽  
Regulatory Mechanisms ◽  
Mesenchymal Transition ◽  
Metastatic Cascade ◽  
Epithelial Phenotype

Epithelial to mesenchymal transition (EMT) occurs during the pathological process associated with tumor progression and is considered to influence and promote the metastatic cascade. Characterized by loss of cell adhesion and apex base polarity, EMT enhances cell motility and metastasis. The key markers of the epithelial to mesenchymal transition are proteins characteristic of the epithelial phenotype, e.g., E-cadherin, cytokeratins, occludin, or desmoplakin, the concentration and activity of which are reduced during this process. On the other hand, as a result of acquiring the characteristics of mesenchymal cells, an increased amount of N-cadherin, vimentin, fibronectin, or vitronectin is observed. Importantly, epithelial cells undergo partial EMT where some of the cells show both epithelial and mesenchymal characteristics. The significant influence of epigenetic regulatory mechanisms is observed in the gene expression involved in EMT. Among the epigenetic modifications accompanying incorrect genetic reprogramming in cancer are changes in the level of DNA methylation within the CpG islands and posttranslational covalent changes of histone proteins. All observed modifications, which are stable but reversible changes, affect the level of gene expression leading to the development and progression of the disease, and consequently affect the uncontrolled growth of the population of cancer cells.

Immunological Relationship Between Plasminogen Activator Inhibitors from Different Sources

1987 ◽  
Vol 57 (01) ◽  
pp. 029-034 ◽  
Author(s):  
Göran Urdén ◽  
Joanna Chmielewska ◽  
Tomas Carlsson ◽  
Björn Wiman
Keyword(s):  
Plasminogen Activator ◽  
Polyclonal Antibodies ◽  
Active Form ◽  
Polyclonal Antiserum ◽  
The Other ◽  
Hep G2 ◽  
Inhibitor Activity ◽  
Tissue Plasminogen ◽  
Immunological Relationship ◽  
Different Sources

SummaryPolyclonal antibodies have been raised against the inhibitor moiety in the purified complex between tissue plasminogen activator and its fast inhibitor (PA-inhibitor) in human plasma/ serum. A radioimmunoassay for quantitation of PA-inhibitor antigen was developed. The polyclonal antiserum and a previously described monoclonal antibody against the PA-inhibitor (14) have been used to study the immunological relationship between PA-inhibitors from plasma, serum, platelets, placenta extract and conditioned media from Hep G2 and HT 1080 cells. It was demonstrated that the ratio between PA-inhibitor activity and antigen varied considerably between the different sources. In the plasma samples studied, similar activity and antigen concentrations were found, suggesting that the PA-inhibitor in these samples mainly was in an active form. On the other hand the other sources seemed to contain variable amounts of inactive PA-inhibitor forms. Immunoadsorption experiments revealed that the PA-inhibitor (activity and antigen) from all the sources were specifically bound to the insolubilized antibodies (polyclonal and monoclonal). In no case, however, could active PA-inhibitor be eluted from the immunoadsorption columns. Also the competitive radioimmunoassays suggested that the PA-inhibitors from the different sources studied, were closely immunologically related.

Thrombotic Thrombocytopenic Purpura: Mechanism for Effectiveness of Plasmapheresis

1979 ◽  
Author(s):  
J. G. Kelton ◽  
P. B. Neame ◽  
I. Walker ◽  
A. G. Turpie ◽  
J. McBride ◽  
...  
Keyword(s):  
Platelet Count ◽  
Thrombotic Thrombocytopenic Purpura ◽  
The Other ◽  
Unknown Etiology ◽  
Normal Range ◽  
Antiplatelet Antibody ◽  
Thrombocytopenic Purpura ◽  
Serious Illness ◽  
Normal Platelet ◽  
Very High

Thrombotic thrombocytopenic purpura (TTP) is a rare but serious illness of unknown etiology. Treatment by plasmapheresis has been reported to be effective but the mechanism for benefit is unknown. We have investigated the effect of plasmapheresis in 2 patients with TTP by quantitating platelet associated IgG (PAIgG) levels prior to and following plasmapheresis. Both patients had very high levels of PAIgG at presentation (90 and A8 fg IgG/platelet respectively, normal 0-5). in both, the PAIgG levels progressively fell to within the normal range and the platelet count rose following plasmapheresis. One patient remained in remission with normal platelet counts and PAIgG levels. The other relapsed after plasmapheresis and the PAIgG level rose prior to the fall in platelet count. Plasmapheresis was repeated and resulted in normalization of both the platelet count and PAIgG level. It is suggested that plasmapheresis removes antiplatelet antibody or immune complexes which may be of etiological importance in this illness.

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