Calcitonin as a tumor marker for nonthyroid neoplasia

Plasma levels of calcitonin have been utilized as a tumor marker for medullary carcinoma of the thyroid. Elevated calcitonin levels have been noted with other tumors as well. The present case documents a marked decrease in calcitonin levels following therapy for breast carcinoma, supporting further evaluation of calcitonin as a clinically useful tumor marker for nonthyroid neoplasm.     

TIMP-1 as a tumor marker in breast cancer--an update

Improvement of the management of breast cancer patients has high priority. In this regard, prognostic stratification needs to be improved in order to ensure proper medical treatment of all patients and furthermore predictors of response to chemotherapy are urgently needed. As new treatment opportunities emerge in the future this need will continue to grow. Thus, the search for molecular markers of prognosis and prediction is ongoing. Tissue Inhibitor of Metalloproteinases-1 (TIMP-1) has been suggested as a marker of both prognosis and response to treatment. Several studies have demonstrated the association between TIMP-1 and prognosis in breast cancer and new studies within this area have focused on the possibility of using blood samples or paraffin embedded tissue instead of tumor tissue extracts for measurements of TIMP-1. Interestingly, recent studies have investigated the association between TIMP-1 and response to treatment showing that TIMP-1 may also carry predictive information on response to treatment. In this regard, results from studies of the molecular functions of TIMP-1 point to a role of TIMP-1 in the inhibition of tumor cell apoptosis as an explanation for the clinical findings. This review gives an update on the ongoing investigation of the potential role of TIMP-1 as a tumor marker in breast cancer. Furthermore, we link the clinical findings with studies of the molecular actions of the TIMP-1 protein, raising hypotheses that may explain why TIMP-1 could play an important role in future management of breast cancer patients.     

Evidence that beta 1-6 branched Asn-linked oligosaccharides on metastatic tumor cells facilitate invasion of basement membranes

In previous studies we have shown that the ability of murine tumor cells to metastasize in situ is directly linked to expression of -GlcNAc beta 1-6Man alpha 1-6Man beta 1-branched complex-type Asn-linked oligosaccharides in tumor-cell glycoproteins. Here we demonstrate that cell-surface expression of beta 1-6 branched oligosaccharides in metastatic tumor cells is specifically associated with increased invasion of human amnion basement membranes in vitro. Compared to nonmetastatic SP1 murine mammary carcinoma cells, 2 metastatic sublines expressed higher levels of beta 1-6 branched oligosaccharides and were found to be invasive but poorly adhesive on the amnion basement membrane. Swainsonine, a non-toxic inhibitor of Asn-linked oligosaccharide processing which blocks the pathway prior to initiation of the beta 1-6 linked antenna, blocked metastatic tumor-cell invasion and increased adhesiveness. Swainsonine and the metalloprotease inhibitor O-phenanthroline inhibited invasion, apparently via independent mechanisms. O-phenanthroline did not affect tumor-cell adhesion to the amnion basement membrane and swainsonine did not block secretion of metalloproteases, beta-hexosaminadase or tissue plasminogen activator activity by the tumor cells. These results suggest that tumor-cell invasion of basement membranes requires both secretion of hydrolase activities and expression of beta 1-6 branched complex-type oligosaccharides at the tumor cell surface, such oligosaccharides being associated with reduced tumor-cell adhesion to extracellular matrix.     

Oncodevelopmental expression of--GlcNAc beta 1-6Man alpha 1-6Man beta 1--branched asparagine-linked oligosaccharides in murine tissues and human breast carcinomas

Increased--GlcNAc beta 1-6Man alpha 1-6Man beta--branching in asparagine-linked oligosaccharides has been observed in murine and human tumor cells and has recently been linked to enhanced metastatic potential in experimental tumor models. Leukoagglutinin (L-PHA) requires the beta 1-6-linked lactosamine antenna (beta 1-6 branch) for high affinity binding and was used in this study to quantitate these structures on glycoproteins separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Normal rodent tissues and cell lines were used to standardize the experimental conditions required to quantitate beta 1-6-branched oligosaccharide structures and the glycosyltransferase activity which initiates the synthesis of the antenna, beta 1-6 N-acetylglucosamine (GlcNAc)-transferase V (EC 2.4.1.155). Secondly, the levels of L-PHA-reactive oligosaccharide were compared in a series of benign and malignant human breast biopsies. Normal human breast tissue and benign lesions showed low expression but 50% of the primary malignancies examined showed significantly elevated L-PHA reactivity. GlcNAc transferase V activities in the human breast carcinomas and in normal murine tissues correlated with the levels of L-PHA reactive oligosaccharide in the tissues. GlcNAc transferase V showed similar ranges of activities, differing by approximately 5-fold between high and low expressing mouse tissues; fibroblasts with and without an activated H-ras oncogene; and low and high expressing human breast carcinomas. The results show that beta 1-6 branching in asparagine-linked oligosaccharides is dependent on tissue-specific regulation of GlcNAc transferase V activity. Secondly, a subset of human breast malignancies showed elevated levels of beta 1-6-branched oligosaccharides compared to benign samples, suggesting that further studies are warranted to determine whether the presence of these oligosaccharides is associated with metastatic disease and reduced patient survival time.     

N-glycoproteins bearing beta1-6 branched oligosaccharides from the A375 human melanoma cell line analysed by tandem mass spectrometry

Tumour-associated alterations of cell surface glycosylation play a crucial role in the adhesion and metastasis of cancer cells. It is well known that the metastatic potential is associated with increased GlcNAc beta1-6 branching in N-glycans of tumour cells specifically recognized by a lectin from Phaseolus vulgaris leukoagglutinin (PHA-L). We identified proteins bearing GlcNAc beta1-6 branched N-glycans in the A375 human melanoma cell line by affinity chromatography separation on a PHA-L agarose column, followed by immunoidentification and tandem mass spectrometry (MS/MS) analysis. Amongst the proteins identified were integrin subunits alpha2, alpha3, alpha5 and beta1, as well as N-cadherin and lysosome-associated membrane proteins (LAMP-1 and LAMP-2). In addition, L1, Mac-2 binding protein (Mac-2-BP), activated leukocyte cell adhesion molecule/CD166 (ALCAM) and melanotransferrin were shown to react with PHA-L. Some of these proteins are connected mainly with nervous tissues or the immune system and play a crucial role in cell adhesion processes. The presence of GlcNAc beta1-6 branched oligosaccharides in these proteins may influence their adhesion properties, reducing adhesion of the cells to the extracellular matrix (ECM) and thus facilitating tumour cell invasion.     

Fatty acid synthase as a tumor marker: its extracellular expression in human breast cancer

Overexpression of fatty acid synthase (FAS EC 2.3.1.85) is associated with certain cancers and therefore is a putative tumor marker. The presence of FAS in patients with breast, prostate, colon, ovarian, and other cancers has been reported. The mechanism of FAS overexpression in malignancies remains unknown. Here, we show that FAS is released into the extracellular space in cancer cells. The extracellular FAS are present in various immunoreactive forms, and show different expression patterns in various cancer cells. In serum of breast cancer patients, the FAS is a small molecule similar to the form in breast cancer cell lysate but not conditioned medium of cultured cells. The extracellular expression of FAS in breast cancer cells is time dependent and may be hormone independent. These results indicate that the FAS are an ordered cellular response of a living cell and actively exclude excess intracellular FAS molecules from the cell. This phenomenon is up-regulated in breast and may be in other cancer cells as well. Significant elevation of FAS was detected in serum of breast cancer patients compared to healthy subjects. In comparison with CA27.29, no correlation between these two tumor markers was found. Thus, the extracellular FAS may serve as a potential diagnostic and prognostic marker.     

Monoclonal antibody 44-3A6 as a marker for breast carcinoma.

The monoclonal antibody (MAb) 44-3A6 detects a 40-kD cell surface protein on adenocarcinomas and may serve as an effective marker for glandular differentiation. Immunohistochemical analysis of 123 paraffin-embedded malignant breast tissue specimens, 27 normal or benign breast disease specimens and 10 atypical hyperplasia specimens from patients without breast cancer was performed with MAb 44-3A6. The antigen was identified in 76% of breast cancer specimens, 0% of normal or benign breast disease specimens and 88% of the atypical hyperplasia specimens. MAb 44-3A6 also detected this antigen on adjacent normal breast ductal cells in 88% of the breast cancer specimens. There was no statistically significant correlation between immunoreactivity and histological mitotic or nuclear grade, recurrence or overall survival. This study suggests that the cell surface antigen detected by the MAb 44-3A6 may serve as an important marker in the differentiation of normal breast epithelium into an atypical or malignant lesion.     

Stromal expression of ALDH1 in human breast carcinomas indicates reduced tumor progression

Interactions between cancer cells and microenvironment are emerging issue in tumor progression. Aldehyde dehydrogenase 1 (ALDH1) is a recognized cancer stem cell marker but little is known about its role in intratumoral stroma. Therefore, we focused on ALDH1 expression in tumor-associated stroma of breast carcinomas (BrCa).Stromal and tumoral ALDH1 expression was evaluated immunohistochemically in BrCa and their lymph node metastases (LNMs), and related to clinico-pathological characteristics, patients’ outcome, presence of CD68, HLADR, retinoic acid (RA) in stroma, and selected proteins in tumor cells.ALDH1(+) stromal cells were detected in 53% of 374 BrCa and 61% of 102 LNMs. ALDH1(+) stroma in primary tumor correlated to longer disease-free (p = 0.030), metastasis-free (p = 0.024), and overall survival (p = 0.043) having an independent prognostic impact on DFS (multivariate analysis, p = 0.047). It was associated with concomitant presence of HLA-DR(+) stromal cells and RA in tumor cells (both p < 0.001), and inversely associated with vimentin expression in tumor cells (p = 0.036). ALDH1(+) stroma in LNMs correlated inversely to presence of disseminated tumor cells in patients’ bone marrow (p = 0.014) and was independent prognosticator of shorter DFS and MFS (multivariate analysis, p = 0.004 and p = 0.002, respectively).In conclusion, ALDH1 expression in tumor-associated stromal cells indicates reduced BrCa progression, possibly via RA secretion.     

Evaluation of serum KL-6, a mucin-like glycoprotein, as a tumor marker for breast cancer.

The utility of serum KL-6 as a tumor marker for breast cancer was evaluated in this study. The sera from 146 patients with breast cancer, 13 with benign breast disease, and 108 healthy individuals were measured for KL-6 titer using a sandwich enzyme immunoassay method. Carcinoembryonic antigen (CEA) and carbohydrate antigen 15-3 (CA15-3) titers were also tested in the same sera from the patients. The mean KL-6 titer of patients with primary breast cancer was 673 units/ml, which was significantly higher than that of benign and healthy individuals (P = 0.037 and P < 0.0001, respectively). The titer of patients with relapsed breast cancer was 1964 units/ml, which was also higher than that of primary cancer (P = 0.013). KL-6 titer was related to tumor stage, distant metastasis, and relapse site (P = 0.0053, P < 0.0001, and P = 0.0251, respectively). Using the cutoff value of 467 units/ml, the sensitivity of KL-6 was 31% for primary breast cancer (16% for stage I and 29% for stage II) and 73% for relapsed breast cancer (50% for local relapse and 89% for distant relapse). The specificity was 92%. The sensitivity of KL-6 was higher than that of CA15-3 and CEA. Combination of the three markers, followed by KL-6 and CEA, raised the sensitivity for primary breast cancer. Single use of KL-6 demonstrated a higher sensitivity than in each combination for relapsed breast cancer. In conclusion, serum KL-6 may be helpful for clinical use as a tumor marker for breast cancer, and it may play an important role, especially in the surveillance of disease relapse.     

TIP60-miR-22 axis as a prognostic marker of breast cancer progression

MicroRNAs (miRNAs) are 22- to 24-nucleotide, small, non-coding RNAs that bind to the 3′UTR of target genes to control gene expression. Consequently, their dysregulation contributes to many diseases, including diabetes and cancer. miR-22 is up-regulated in numerous metastatic cancers and recent studies have suggested a role for miR-22 in promoting stemness and metastasis. TIP60 is a lysine acetyl-transferase reported to be down-regulated in cancer but the molecular mechanism of this reduction is still unclear. In this study, we identify TIP60 as a target of miR-22. We show a negative correlation in the expression of TIP60 and miR-22 in breast cancer patients, and show that low levels of TIP60 and high levels of miR-22 are associated with poor overall survival. Furthermore, pathway analysis using high miR-22/low TIP60 and low miR-22/high TIP60 breast cancer patient datasets suggests association of TIP60/miR-22 with epithelial-mesenchymal transition (EMT), a key alteration in progression of cancer cells. We show that blocking endogenous miR-22 can restore TIP60 levels, which in turn decreases the migration and invasion capacity of metastatic breast cancer cell line. These results provide mechanistic insight into TIP60 regulation and evidence for the utility of the combination of TIP60 and miR-22 as prognostic indicator of breast cancer progression.     

ERCC1 expression as a molecular marker of cisplatin resistance in human cervical tumor cells

Cisplatin is a valuable adjuvant to radiotherapy for the treatment of cervical cancer. Because the advantage of combining cisplatin with radiotherapy is likely to be attributable to additive cell killing by these 2 agents, such protocols should primarily benefit patients who have inherently cisplatin-sensitive tumors. Development of a molecular assay to rapidly evaluate the cisplatin responsiveness of cervical tumors would thus be extremely valuable. We investigated whether high pre-treatment mRNA levels of the ERCC1 nucleotide excision repair gene are predictive of cisplatin resistance in early-passage human cervical cancer cells, as they are in several other tumor types. Expression of the ERCC1 gene at the mRNA and protein levels was established by Northern and Western blotting, respectively, in a panel of single-cell-derived cervical carcinoma cell lines that exhibited a wide range of inherent sensitivity to cisplatin. There was a significant (p 相似文献   

hSTC-1作为肿瘤标志物的研究

斯钙素(stanniocalcin,STC)是一种首先在硬骨鱼中发现的糖蛋白激素,该激素由鱼类独有的内分泌腺斯坦尼氏小体所分泌。近年来发现人和其它哺乳动物也存在STC,有STC-1和STC-2两种。有研究探讨了hSTC-1作为肿瘤标志物的可行性,本文主要就hSTC-1作为肿瘤标志物的研究作一综述。     

hSTC-1作为肿瘤标志物的研究

斯钙素（stanniocalcin,STC）是一种首先在硬骨鱼中发现的糖蛋白激素,该激素由鱼类独有的内分泌腺斯坦尼氏小体所分泌。近年来发现人和其它哺乳动物也存在STC,有STC-1和STC-2两种。有研究探讨了hSTC-1作为肿瘤标志物的可行性,本文主要就hSTC-1作为肿瘤标志物的研究作一综述。