Potential Marker For Metastasis Research Articles

Serum Osteopontin as a Potential Marker for Metastasis and Prognosis in Primary Osteogenic Sarcoma: A Systematic Review.

Osteosarcoma (OS), a primary malignant bone tumor, poses significant challenges in diagnosis and prognosis. It is a painful medical burden, and treating it is still a difficult issue. Osteopontin (OPN), a multifunctional extracellular matrix protein, has emerged as a promising biomarker in this context. This systematic review explores the role of OPN as a diagnostic and prognostic marker in OS, highlighting its potential in enhancing early detection, monitoring disease progression, and predicting patient outcomes. Various studies have demonstrated elevated levels of OPN in OS patients, correlating with tumor aggressiveness, metastatic potential, and poor prognosis. In addition, OPN's involvement in tumor microenvironment regulation and metastatic processes underscores its clinical relevance as a biomarker. For this systematic review, comprehensive literature searches were conducted in the PubMed databases for researchpublished between the database's establishment and November 11, 2022. Out of the nine studies that were available for analysis, a higher level of OPN in primary osteogenic sarcoma patients indicates a poorer prognosis and higher incidence of metastasis. OS has not shown commensurable progress with concerns to treatment approches and survical outcomes. However, the discovery of a biological marker that can predict metastasis and severity will be a groundbreaking development for advancements in OS diagnosis and treatment. Therefore, understanding the intricate interplay between OPN and OS pathogenesis holds promise for improving patient management and developing targeted therapeutic strategies.

ABCA1 transporter promotes the motility of human melanoma cells by modulating their plasma membrane organization

BackgroundMelanoma is one of the most aggressive and deadliest skin tumor. Cholesterol content in melanoma cells is elevated, and a portion of it accumulates into lipid rafts. Therefore, the plasma membrane cholesterol and its lateral organization might be directly linked with tumor development. ATP Binding Cassette A1 (ABCA1) transporter modulates physico-chemical properties of the plasma membrane by modifying cholesterol distribution. Several studies linked the activity of the transporter with a different outcome of tumor progression depending on which type. However, no direct link between human melanoma progression and ABCA1 activity has been reported yet.MethodsAn immunohistochemical study on the ABCA1 level in 110 patients-derived melanoma tumors was performed to investigate the potential association of the transporter with melanoma stage of progression and prognosis. Furthermore, proliferation, migration and invasion assays, extracellular-matrix degradation assay, immunochemistry on proteins involved in migration processes and a combination of biophysical microscopy analysis of the plasma membrane organization of Hs294T human melanoma wild type, control (scrambled), ABCA1 Knockout (ABCA1 KO) and ABCA1 chemically inactivated cells were used to study the impact of ABCA1 activity on human melanoma metastasis processes.ResultsThe immunohistochemical analysis of clinical samples showed that high level of ABCA1 transporter in human melanoma is associated with a poor prognosis. Depletion or inhibition of ABCA1 impacts invasion capacities of aggressive melanoma cells. Loss of ABCA1 activity partially prevented cellular motility by affecting active focal adhesions formation via blocking clustering of phosphorylated focal adhesion kinases and active integrin β3. Moreover, ABCA1 activity regulated the lateral organization of the plasma membrane in melanoma cells. Disrupting this organization, by increasing the content of cholesterol, also blocked active focal adhesion formation.ConclusionHuman melanoma cells reorganize their plasma membrane cholesterol content and organization via ABCA1 activity to promote motility processes and aggressiveness potential. Therefore, ABCA1 may contribute to tumor progression and poor prognosis, suggesting ABCA1 to be a potential metastatic marker in melanoma.

Abstract P6-12-11: Feasibility and biomarker modulation due to high levels of moderate to vigorous physical activity as part of a weight loss intervention in older, sedentary, obese breast cancer survivors

Abstract We sought to demonstrate that older, sedentary, obese breast cancer survivors could achieve > 200 minutes per week of moderate to vigorous physical activity (MVI PA) as part of a weight loss intervention; and to assess modulation of risk biomarkers. This level of PA in combination with moderate calorie restriction is associated with weight losses of >10% in women without cancer, which in turn is associated with significant modulation of cancer risk biomarkers. Eleven participants with BMI > 30 kg/m2 enrolled in a 12-week program that consisted of moderate caloric restriction, weekly phone group behavioral sessions, and individualized exercise plans based on measured heart rate reserve. Women were provided an accelerometer with heart rate monitor linked to GarminConnect, membership to a YMCA, twice weekly supervised exercise sessions with a personal trainer, and weekly feedback regarding weight and physical activity progress. The goal was to increase MVI PA (≥45% heart rate reserve) gradually from <60 to >200 minutes per week. The median age was 61, 5/11 women had received prior chemotherapy, and 7/11 were currently taking aromatase inhibitors. Median values of baseline anthropomorphic measures acquired by dual energy x-ray absorptiometry (GE Lunar iDXA) included BMI, 37.3 kg/m2; total mass, 97.5 kg; fat mass, 47.6 kg; visceral fat, 1.7 kg (range 1.4-3.0); and fat mass index, 17.6 kg/m2. The majority had a baseline VO2 peak in the poor range for their age. All 11 participants completed the intervention, with no reported serious adverse events. Median MVI PA achieved over weeks 5-12 was 161 minutes/week (range 48-320). VO2 peak was increased in 10/11 with a median relative change of 12% from baseline. All but one lost weight with an overall median of 8% total mass loss, which was associated with 13% total fat mass loss and 21% visceral fat mass loss. For those with MVI PA above the median, values were 11%, 17%, and 40%, respectively. Visceral fat mass loss was linearly correlated with minutes per week of MVI PA (p=0.032); these parameters in turn were associated with changes in a number of serum biomarkers, including adiponectin-leptin ratio, TNF-alpha, as well as circulating adipose stromal cells, a potential marker for metastasis. Insulin and hs-CRP were favorably modulated in almost all participants but change was not linearly correlated with activity or mass loss parameters; thus these may not be ideal biomarkers to document a dose response to level of MVI PA. Conclusion: These results demonstrate that older, sedentary, obese breast cancer survivors can safely achieve a high level of MVI PA when provided a structured program that includes an exercise trainer. It is feasible to design a clinical trial for such breast cancer survivors to examine biomarker modulation as a function of level of physical activity. Citation Format: Fabian CJ, Klemp JR, Burns JM, Vidoni ED, Nydegger JL, Kreutzjans AL, Phillips TL, Baker HA, Hendry B, John C, Amin AL, Khan QJ, Mitchell MP, O'Dea AP, Sharma P, Wagner JL, Hursting SD, Kimler BF. Feasibility and biomarker modulation due to high levels of moderate to vigorous physical activity as part of a weight loss intervention in older, sedentary, obese breast cancer survivors [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-12-11.

GTSE1: a novel TEAD4-E2F1 target gene involved in cell protrusions formation in triple-negative breast cancer cell models.

GTSE1 over-expression has been reported as a potential marker for metastasis in various types of malignancies, including breast cancer. Despite this, the transcriptional regulation of this protein and the causes of its misregulation in tumors remain largely unknown. The aims of this work were to elucidate how GTSE1 is regulated at the transcriptional level and to clarify the mechanism underlying GTSE1-dependent cell functions in triple-negative breast cancer (TNBC).Here, we identified GTSE1 as a novel target gene of the TEAD4 transcription factor, highlighting a role for the YAP and TAZ coactivators in the transcriptional regulation of GTSE1.Moreover, we found that TEAD4 controls the formation of cell protrusions required for cell migration through GTSE1, unveiling a relevant effector role for this protein in the TEAD-dependent cellular functions and confirming TEAD4 role in promoting invasion and metastasis in breast cancer.Finally, we highlighted a role for the pRb-E2F1 pathway in the control of GTSE1 transcription and observed that treatment with drugs targeting the pRb-E2F1 or YAP/TAZ-TEAD pathways dramatically downregulated the expression levels of GTSE1 and of other genes involved in the formation of metastasis, suggesting their potential use in the treatment of TNBC.

MiR-301a expression: A prognostic marker for prostate cancer

PurposeThe diagnosis and treatment of prostate cancer (CaP) continues to be challenging, as prostate-specific antigen (PSA) appears to be overly sensitive and biopsy is the only reliable method for confirmation. Hence, the goal of the study is to identify a biomarker that could distinguish malignant cancer from benign prostatic hyperplasia (BPH) during the early diagnosis of the disease. Materials and methodsA total of 75 formalin fixed paraffin embedded (FFPE) with matching controls, 4 paired metastatic tumors, 6 fresh tumor tissues and BPH (13 cases) with their clinical diagnosis were selected for this study. Prostate cancer cell lines and normal prostate epithelial cell lines were obtained from ATCC and subjected to phenotypic analysis. ResultsWe observed significant differential expression of miR-301a in CaP samples in comparison to BPH and adjacent benign samples. The overexpression of miR-301a activates the invasion/migration of CaP cells. In contrast, silencing miR-301a expression inhibited the colony-forming ability, adhesion, invasion and migration of CaP cells. Similarly, the overexpression of miR-301a increased cell motility in normal RWPE-1 prostate epithelial cells. Our results suggest that miR-301a is differentially expressed between BPH and CaP specimens and that the expression of miR-301a correlates with biochemical recurrence and/or metastasis in CaP patients. ConclusionsThe expression of miR-301a could be a potential marker for metastasis in CaP patients. Detecting miR-301a expression during diagnosis will avoid wait and watch timelines, thus preventing morbidity.

Determining the Role of Oxysterol Binding Protein‐Related Protein 4 (ORP4) in Cell Proliferation and Survival

Oxysterol binding protein (OSBP) and related proteins (ORPs) constitute a 12-member family of mammalian lipid binding proteins with diverse cellular expression, localization and ligands. ORP4 is closely related to OSBP and expressed as short (ORP4S), medium (ORP4M) and long (ORP4L) isoforms as a result of alternate transcription start sites. ORP4 was initially discovered in disseminated tumor cells and considered a potential marker of metastasis. We recently showed that lentiviral short-hairpin RNA silencing of ORP4 induced cell-specific growth arrest or apoptosis. To determine how ORP4 promotes cell proliferation and survival, we identified relevant signaling pathways that are activated upon ORP4 silencing. In HeLa cells, ORP4 silencing was accompanied by elevated expression of p21 and phospho-p53 isoforms as well as cell cycle arrest but not apoptosis. ORP4 silencing also induced growth arrest in HEK 293 cells but triggered apoptosis in non-transformed rat intestinal epithelial cells. A potential role for ORP4L in genomic stability is indicated by its interaction with a component of the Mis18 complex required for centromere organization. Mass spectrometry was used to identify a MAPK phosphorylation site in the C-terminal lipid-binding domain of ORP4L. An ORP4L phospho-mimetic (serine-to-glutamate) MAPK site mutant expressed in HeLa cells was associated with an aggregated vimentin network, which was not observed with the corresponding serine-to-alanine mutant or wild-type ORP4L. These data suggest that ORP4L phosphorylation by MAPK enhances its interaction with the cytoskeleton and/or genomic regulators, ultimately affecting p21/p53-dependent control of cell cycle progression.

Loss of E-cadherin promotes migration and invasion of cholangiocarcinoma cells and serves as a potential marker of metastasis.

Tumor progression is characterized by loss of cell adhesion and increase of invasion and metastasis. E-cadherin, a cell adhesion molecule, is frequently downregulated and has been proposed as an important mediator in epithelial-mesenchymal transition (EMT) in tumors. In this study, we investigated the expression of E-cadherin and its association with cancer invasion and prognosis in cholangiocarcinoma (CCA). Immunohistochemistry results demonstrated a statistically significant association between the positive metastasis status with low E-cadherin protein expression in human CCA tissues (P = 0.04). Statistical trends were identified for low E-cadherin level and shorter survival time (P = 0.08). Targeting the E-cadherin expression in CCA cells with siRNA caused upregulation of vimentin, a mesenchymal marker, and disappearance of the E-cadherin/β-catenin adhesion complex from cell membranes. Moreover, migration and invasion abilities of the cells were increased under this condition. These findings suggest that reduction of E-cadherin contributes to CCA progression by attenuating the strength of cellular adhesion, which affects motility as well as regulating the expression of EMT-related genes during CCA invasion and metastasis. Thus, E-cadherin can act as a central modulator of tumor cell phenotype and is a potential metastasis marker in CCA.

EZH2 is regulated by ERK/AKT and targets integrin alpha2 gene to control Epithelial–Mesenchymal Transition and anoikis in colon cancer cells

Epithelial–Mesenchymal Transition is a good example of cell plasticity. In tumorigenesis, this process has been associated with metastasis. Overexpression of EZH2 has been detected in most malignant human tumors, including colorectal carcinomas. Herein, we provide evidence supporting the idea that oncogenic Epithelial–Mesenchymal Transition in colon cancer cell models is partially controlled by epigenetic factors such as the transcription regulator EZH2. Evaluation of EZH2 mRNA and protein levels revealed overexpression in cell lines with metastatic traits. Analysis of EZH2 mRNA expression was expanded in clinical samples of colon cancer, and high level of EZH2 correlates with appearance of metastasis. Furthermore, inhibition of ERK and AKT pathways in metastatic colon cancer cell lines attenuates EZH2 overexpression. EZH2 promoter analysis illustrates presence of putative AP-1 binding sites and occupancy of transcription factors such as FRA-1 and C-JUN is demonstrated here on EZH2 promoter. Abrogation of EZH2 expression impairs the ability of colon cancer cells to move associated with anoikis in three-dimensional environment. Integrin alpha2 was identified to be a novel EZH2 target by chromatin immunoprecipitation and short hairpin RNA analysis. This study proposes that activation of ERK/AKT pathways and FRA1/C-JUN induce EZH2 overexpression, which results in Integrin alpha2 silencing. Our results show how deregulation of epigenetic factors and mechanisms can affect cancer cell aggressiveness and propose EZH2 as a potential metastasis marker and/or therapeutic target for colorectal cancer treatment.

Expression of transgelin-2 and clinical significance in colorectal cancer

To investigate the relationship between the expression of transgelin-2 and the clinicopathological factors of colorectal carcinoma and evaluate the value of transgelin-2 in prognostic assessment of the colorectal cancer patients. Using tissue microarray and immunohistochemical methods, we examined transgelin-2 of 120 colorectal cancer patients received surgical treatment from September 2002 to April 2004, including 74 male and 46 female, age from 26 to 89 years. Analyzed the relationship between transgelin-2 and both the clinicopathological features and prognosis of the colorectal cancer by using χ² test and Kaplan-Meier survival analysis. Cox proportion hazard regression analysis was used to study the independent prognostic factors. The positive rate of transgelin-2 expression was 69.2% in colorectal carcinoma. The transgelin-2 expression correlated with differentiation degree (χ² = 5.420), lymph nodes metastasis (χ² = 45.577), distant metastasis (χ² = 12.009), and TNM staging (χ² = 47.577). The survival time was (39 ± 5) months in patients with positive expression of the transgelin-2, while (59 ± 3) months in patients with negative expression. The patient's survival time was statistically correlated with the transgelin-2 expression (P = 0.003). Distant metastasis (RR = 8.318, 95%CI: 4.119 - 16.790), lymph nodes metastasis (RR = 2.794, 95%CI: 1.246 - 6.263) and transgelin-2 expression (RR = 1.834, 95%CI: 1.118- 2.973) were independent prognostic factors in patients with colorectal cancer (P < 0.05). The expression of transgelin-2 is correlated with clinicopathological features and prognosis in colorectal cancer, may be the potential marker of metastasis and the prognosis of colorectal cancer patients.

Identification and Metastatic Potential of Tumor-Initiating Cells in Malignant Rhabdoid Tumor of the Kidney

Malignant rhabdoid tumor of the kidney (MRTK) is a rare and highly aggressive malignancy of infanthood. In an effort to delineate MRTK progression, we investigated the metastatic fate of some MRTK cells using xenotransplantation animal models and the tumor-initiating potential of CD133(+) MRTK cells. We established two MRTK cell lines (JMU-RTK-1 and JMU-RTK-2) from patients with MRTK. We generated five luciferase-expressing MRTK cells for in vivo luminescent imaging and evaluated the metastatic fate in an orthotopic xenotransplantation model. Capacities of MRTK-initiating cells were examined in nonobese diabetic/severe combined immunodeficient mice after antibody-mediated magnetic bead sorting. Use of chemokine receptor CXCR4 expression as a metastatic marker was evaluated by flow cytometry and Western blotting. MRTK cell lines showed distant organ metastasis. JMU-RTK-1, JMU-RTK-2, and G401 cells showed considerable aggressiveness compared with SWT-1 and SWT-2 cells (P < 0.05). Moreover, as few as 1,000 CD133(+) MRTK cells initiated tumor development in nonobese diabetic/severe combined immunodeficient mice by 21 days (60-100%) in all examined cell lines, although the same number of CD133(-) MRTK cells could not form tumors (0%). Interestingly, the metastatic potential of the CD133(+) population remained unaffected compared with a nonenriched population. The potential metastatic marker CXCR4 was expressed in CD133(+) and CD133(-) MRTK cells, and CD133(-) cells seemed to play a cooperative role in terms of tumorigenicity and metastasis. These results suggest that CD133(+) cells may determine the metastatic fate of MRTK cells and that CD133(-) cells may play an auxiliary role in tumor progression and metastasis.

218: Uniparental Polysomy of Chromosome 3Q is a Potential Metastatic Marker in the Patient with Clear Cell Renal Cell Carcinoma

218: Uniparental Polysomy of Chromosome 3Q is a Potential Metastatic Marker in the Patient with Clear Cell Renal Cell Carcinoma

Differential Expression of the L-Plastin Gene in Human Colorectal Cancer Progression and Metastasis

To identify molecular alterations in the progression of colorectal carcinoma, we analyzed gene expression profiles of colon cancer cell lines derived from primary and metastatic tumors from a single patient. Of 2280 cDNAs investigated using our in-house microarray, the expression of 6 genes (tumor-associated antigen L6, L-plastin, the human homologue of yeast ribosomal protein S28, the B-cell translocation gene, mitochondrial aspartate-aminotransferase, and HLA-A) increased, while that of 2 genes (keratin 5 and phosphoglucomutase) decreased in metastatic-tumor-derived cells compared with primary-tumor-derived cells. Of these genes, we assessed the L-plastin gene, an actin-bundling protein, at the protein level using a tissue microarray consisting of 58 clinically stratified colorectal cancer specimens. Consistent with our microarray results, the expression of L-plastin was significantly correlated with the progression of cancer staging. Therefore, our results suggest that the L-plastin gene is a potential metastatic marker. In addition, combining cDNA microarrays and tissue arrays, as shown here, is thought to facilitate the rapid characterization of candidate biomarkers.

Integrin expression on cell adhesion function and up-regulation of P125FAK and paxillin in metastatic renal carcinoma cells.

Integrins from normal human renal cortex epithelial cells (RCEC) and from four renal carcinoma lines (metastatic Caki-1, non-metastatic Caki-2, metastatic ACHN, and non-metastatic 769-P) were compared by immunoprecipitation with specific anti-integrin antibodies. Integrin alpha 2 was present in normal RCEC, but absent in all four tumor lines. There was a 2.0-3.0 fold decrease of alpha 3 and beta 1 in localized tumor lines, and a further 5.0-7.0 fold decrease in metastatic lines over their expression in normal renal cells. No alpha V was detected in Caki-1 cells. The greatest adhesion of all cells occurred in the presence of a stimulatory anti-alpha 3 antibody, mediated by specific matrix proteins employed as substrates, while anti-beta 1 treatment dramatically inhibited cell attachment on collagen IV, plasma fibronectin, laminin and merosin substrates. In addition, the mRNA expression of focal adhesion kinase (p125FAK) and paxillin were up-regulated (2.0-2.5 fold increase) in the metastatic Caki-1 cells over normal RCEC. The alteration of integrin subunits alpha 2, alpha 3, alpha V, beta 1, as well as p125FAK and paxillin may contribute to the pathogenicity and/or metastatic propensity of renal epithelial tumors. The up-regulation of paxillin independently or in concert with p125FAK as shown in this study indicates its significant role as a potential marker of metastasis in renal carcinoma cells.