Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cancer progression is associated with reduced apoptosis and increased proliferation. We hypothesized that upregulation of the Bag family of survival cochaperones and its molecular partners of the Bcl-2 and heat shock protein (HSP) families would correlate with disease progression and survival in ovarian cancer. Bag-1, Bag-4, HSP27, HSP70, Bcl-2, and Bcl-X(L) expression was immunohistochemically analyzed in effusions (188) and patient-matched solid tumors (43 primary carcinomas, 81 solid metastases). Results were analyzed for anatomic site-related differences, and association with clinicopathologic parameters and survival. Bag-1, Bag-4, and HSP70 were detected in the tumor cell nuclei and cytoplasm, whereas HSP27, Bcl-2, and Bcl-X(L) had exclusively cytoplasmic localization. Antiapoptotic protein expression in effusions differed significantly from primary tumors and metastases. Cytoplasmic Bag-1 (P=0.002), nuclear and cytoplasmic HSP70 (P<0.001), and Bcl-2 (P=0.001) expression was higher in primary carcinomas and solid metastases compared with effusions, whereas Bcl-X(L) (P=0.01), nuclear Bag-1 (P<0.001), nuclear Bag-4 (P=0.01), and cytoplasmic Bag-4 (P=0.002) were upregulated in effusions. Bcl-X(L) expression was associated with poor response to chemotherapy at diagnosis (P=0.02) and HSP27 expression was associated with high-grade tumors (P=0.01). Increased cytoplasmic HSP70 staining in effusions correlated with poor overall survival for the entire cohort (P=0.01). In primary carcinomas, higher Bcl-2 expression correlated with worse overall (P=0.04) and progression-free (P=0.02) survival. Antiapoptotic proteins are differentially expressed in effusions compared with solid tumors, whereas primary carcinomas and solid metastases have comparable expression patterns. HSP70 expression in effusions may be a prognostic marker of poor survival, with a similar role for Bcl-2 in primary carcinomas.
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PMID:Expression and clinical role of antiapoptotic proteins of the bag, heat shock, and Bcl-2 families in effusions, primary tumors, and solid metastases in ovarian carcinoma. 1962 Sep 38

Hsp70, the major stress-inducible member of the 70 kDa heat shock protein family, is frequently exposed on the plasma membrane of human tumours and, even more pronounced, on metastases but not detectable on normal tissues. The mouse monoclonal antibody cmHsp70.1, which recognizes a peptide epitope in the C-terminal substrate binding domain of both human and murine Hsp70, provides a promising reagent for the monitoring of Hsp70-positive tumours during cancer therapy. Here, we describe the variable domain sequences of the antibody produced by the hybridoma cell line and attempts to secrete the corresponding recombinant Fab fragment in Escherichia coli. Initially, the yield of soluble functional Fab fragment that could be purified from the periplasmic cell extract was extremely low, even when preparing different chimeric versions with constant domains of human or murine origin or with the light chain constant domain belonging to the kappa or lambda class. Surprisingly, this yield could be raised dramatically by more than a factor 100 in the presence of the folding helper plasmid pTUM4, which overexpresses two periplasmic disulphide oxido-reductases as well as two chaperones with proline-cis/trans-isomerase activity. Thus, more than 15 mg functional recombinant Fab fragment could be purified per litre E.coli culture from a bench top fermenter. This Fab fragment showed high and specific Hsp70 binding activity in ELISA and SPR measurements, revealing a dissociation constant of 35 nM. Notably, the Fab fragment sensitively recognizes the membrane-associated Hsp70 on tumour cell lines both in immunofluorescence microscopy and flow cytometry, thus showing potential for tumour detection in vitro and in vivo.
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PMID:Bacterial production and functional characterization of the Fab fragment of the murine IgG1/lambda monoclonal antibody cmHsp70.1, a reagent for tumour diagnostics. 2012 84

HCT-8 colon cancer cells secreted heat shock protein 90alpha (HSP90alpha) and had increased invasiveness upon serum starvation. The concentrated conditioned medium of serum-starved HCT-8 cells was able to stimulate the migration and invasion of non-serum-starved cells, which could be prevented by treatment with an anti-HSP90alpha antibody. Recombinant HSP90alpha (rHSP90alpha) also enhanced HCT-8 cell migration and invasion, suggesting a stimulatory role of secreted HSP90alpha in cancer malignancy. HSP90alpha binding to CD91alpha and Neu was evidenced by the proximity ligation assay, and rHSP90alpha-induced HCT-8 cell invasion could be suppressed by the addition of anti-CD91alpha or anti-Neu antibodies. Via CD91alpha and Neu, rHSP90alpha selectively induced integrin alpha(V) expression, and knockdown of integrin alpha(V) efficiently blocked rHSP90alpha-induced HCT-8 cell invasion. rHSP90alpha induced the activities of ERK, PI3K/Akt, and NF-kappaB p65, but only NF-kappaB activation was involved in HSP90alpha-induced integrin alpha(V) expression. Additionally, we investigated the serum levels of HSP90alpha and the expression status of tumor integrin alpha(V) mRNA in colorectal cancer patients. Serum HSP90alpha levels of colorectal cancer patients were significantly higher than those of normal volunteers (p < 0.001). Patients with higher serum HSP90alpha levels significantly exhibited elevated levels of integrin alpha(V) mRNA in tumor tissues as compared with adjacent non-tumor tissues (p < 0.001). Furthermore, tumor integrin alpha(V) overexpression was significantly correlated with TNM (Tumor, Node, Metastasis) staging (p = 0.001).
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PMID:Secreted heat shock protein 90alpha induces colorectal cancer cell invasion through CD91/LRP-1 and NF-kappaB-mediated integrin alphaV expression. 2055 45

The current standard treatment for early stage (I-III) renal cell cancer (RCC) is surgery. While the prognosis of stage I tumors is excellent, stage II and particularly stage III have a high risk of relapse. The adjuvant treatment of patients with RCC remains an area of investigation, with patient selection being a key aspect. There are currently two prognostic nomograms to establish the risk of relapse in patients with resected RCC. The results of earlier studies of adjuvant therapy, including the use chemotherapy and/or immunotherapy after nephrectomy have failed to show any benefit in the outcome of patients at risk of developing local recurrence or distant metastases. Two recent phase III trials with vaccines (autologous tumor cell vaccine and autologous tumor-derived heat shock protein peptide complex-96) have shown promising, albeit still preliminary, results. In the metastatic RCC setting, recent advances in the molecular understanding of oncogenic pathways have led to the development of new therapeutic strategies with the use of targeted therapies in the adjuvant setting. Neoadjuvant treatment is another treatment modality currently being evaluated for patients with early disease and in patients with metastatic RCC with inoperable primary tumors. The questions that remain unanswered include activity of these agents in early stages of the disease, patient selection, optimal start time of the adjuvant treatment, and finally, the optimal length of treatment.
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PMID:Neoadjuvant and adjuvant strategies in renal cell carcinoma: more questions than answers. 2117 4

Canine mammary sarcomas are usually very aggressive and easily metastasize. Unfortunately the biology of this type of tumor is not well known because they are a very rare type of tumors. The aim of this study was to find differences in gene expression patterns in canine mammary osteosarcomas (malignant) versus osteomas (benign) using DNA microarrays. Our microarray experiment showed that 11 genes were up-regulated in osteosarcoma in comparison to osteoma whereas 36 genes were down-regulated. Among the up-regulated genes were: PDK1, EXT1, and EIF4H which are involved in AKT/PI3K and GLI/Hedgehog pathways. These genes play an important role in cell biology (cancer cell proliferation) and may be essential in osteosarcoma formation and development. Analyzing the down-regulated genes, the most interesting seemed to be HSPB8 and SEPP1. HSPB8 is a small heat shock protein that plays an important role in cell cycle regulation, apoptosis, and breast carcinogenesis. Also SEPP1 may play a role in carcinogenesis, as its down-regulation may induce oxidative stress possibly resulting in carcinogenesis. The preliminary results of the present study indicate that the up-regulation of three genes EXT1, EIF4H, and PDK1 may play an essential role in osteosarcoma formation, development and proliferation. In our opinion the cross-talk between GLI/Hedgehog and PI3K/AKT pathways may be a key factor to increase tumor proliferation and malignancy.
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PMID:Gene expression pattern in canine mammary osteosarcoma. 2152 6

The hepatocyte growth factor (HGF) also known as scatter factor activates cancer cell invasion and metastasis. We show that in ovarian cancer cells HGF induced the phosphorylation of the small heat shock protein of 27 kDa (HSP27) by activating the p38MAPK. HSP27 is increased in many cancers at advanced stage including ovarian cancer and associated with cancer resistance to therapy and poor patients' survival. The phosphorylation of HSP27 regulates both its chaperone activity and its control of cytoskeletal stability. We show that HSP27 was necessary for the remodeling of actin filaments induced by HGF and that motility in vitro depended on the p38MAPK-MK2 axis. In vivo, HSP27 silencing impaired the ability of the highly metastatic, HGF-secreting ovarian cancer cells to give rise to spontaneous metastases. This was due to defective motility across the vessel wall and reduced growth. Indeed, HSP27 silencing impaired the ability of circulating ovarian cancer cells to home to the lungs and to form experimental hematogenous metastases and the capability of cancer cells to grow as subcutaneous xenografts. Moreover, HSP27 suppression resulted in the sensitization of xenografts to low doses of the chemotherapeutic paclitaxel, likely because HSP27 protected microtubules from bundling caused by the drug. Altogether, these data show that the HSP27 is required for the proinvasive and prometastatic activity of HGF and suggest that HSP27 might be not only a marker of progression of ovarian cancer, but also a suitable target for therapy.
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PMID:HSP27 is required for invasion and metastasis triggered by hepatocyte growth factor. 2399 44

Ovarian cancer is the major gynaecologic malignancy and the leading cause of death in gynaecological cancer. Heat shock proteins (HSPs) are highly expressed in many malignant cancers and involved in metastasis including ovarian cancer. The early detection of peritoneal metastases in epithelial ovarian cancer may be more important in clinical care. HSP27, a small heat shock protein, is correlated with peritoneal metastases in epithelial ovarian cancer tissues. In this study, we investigated whether the levels of total HSP27 were detectable in serum and whether it could be a predictive biomarker for peritoneal metastases in epithelial ovarian cancer. Serum samples from 48 patients with epithelial ovarian cancer, 35 patients with benign ovarian tumours and 24 healthy women were included in this study. The serum levels of total HSP27 were measured by enzyme-linked immunosorbent assay (ELISA). There was no difference in the serum levels of total HSP27 between women with benign ovarian tumours and healthy women. However, the serum levels of total HSP27 were significantly increased in patients with epithelial ovarian cancer. The increased serum levels of total HSP27 were only seen in patients with peritoneal metastases. Furthermore, increased serum levels of total HSP27 were significantly reduced after the combination chemotherapies in patients with peritoneal metastases. These data suggest that circulating HSP27 levels were increased in epithelial ovarian cancer and correlated with peritoneal metastases. The measurement of serum HSP27 levels may be used as a potential additional indicator for peritoneal metastases in epithelial ovarian cancer and response to treatment.
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PMID:Heat shock protein 27: a potential biomarker of peritoneal metastasis in epithelial ovarian cancer? 2406 37

Matrix metalloproteinase 2 (MMP-2) in metastatic cancer tissue, which is associated with a poor prognosis, is a potential target for tumor imaging in vivo. Here, we describe a metastatic cancer cell-targeted protein nanocage. An MMP-2-binding peptide, termed CTT peptide (CTTHWGFTLC), was conjugated to the surface of a naturally occurring heat shock protein nanocage by genetic modification. The engineered protein nanocages showed a binding affinity for MMP-2 and selective uptake in cancer cells that highly expressed MMP-2 in vitro. In near-infrared fluorescence imaging, the nanocages showed specific and significant accumulation in tumor tissue after intravenous injection in vivo. These protein nanocages conjugated with CTT peptide could be potentially applied to a noninvasive near-infrared fluorescence detection method for imaging gelatinase activity in metastatic tumors in vivo.
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PMID:Systemic delivery of protein nanocages bearing CTT peptides for enhanced imaging of MMP-2 expression in metastatic tumor models. 2554 85

Prostate cancer (PCa) is a hormone-sensitive disease. Androgen deprivation therapy lowers serum testosterone levels (castration) or blocks the androgen receptor (AR) ligand-binding domain. Especially in metastatic disease, hormonal therapy has been able to delay disease progression, reduce symptoms, and improve overall survival. Despite subsequent disease progression and development of castration resistance, PCa remains AR driven. Secondary hormonal treatments such as abiraterone acetate or enzalutamide have demonstrated increased overall survival. However, new resistance mechanisms to these agents have been identified, and systemic chemotherapy is still needed especially in fast-progressing castration-resistant PCa. Several promising androgen synthesis inhibitors (orteronel and galeterone), AR inhibitors (ARN-509, EPI-001, AZD3514, and ODM-201), and heat shock protein modulators (AT11387, 17-DMAG, STA-9090, and OGX-427) are currently under investigation. The wide variety in upcoming systemic agents underlines the molecular heterogeneity of castration-resistant PCa. This article reviews antihormonal therapy in PCa and resistance mechanisms and focuses on novel and upcoming agents currently in clinical testing.
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PMID:Battling resistance mechanisms in antihormonal prostate cancer treatment: Novel agents and combinations. 2570 54

Radiotherapy represents an essential treatment option for the majority of cancer patients in different stages of their disease. Physical achievements of the recent years led to the implementation of high precision treatment planning procedures, and image-guided dose delivery is current state of the art. Yet, radiotherapy still faces several limitations with cancer intrinsic radioresistance being a key driver of therapeutic failure. Accordingly, the mechanisms orchestrating radioresistance and their therapeutic targeting by combined modality approaches are in the center of attention of numerous radiation oncologists. In the present review, we summarize and discuss therapeutic approaches that exploit the heat shock response, either by hyperthermia or by pharmacological heat shock protein inhibition, in combination with radiotherapy. These strategies appear particularly promising, since they sensitize cancer cells to irradiation-induced cell death and at the same time have proven the potential to promote systemic anti-tumor immune mechanisms, which may target not only locally surviving tumor cells, but also distant out-of-field metastases.
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PMID:Targeting the heat shock response in combination with radiotherapy: Sensitizing cancer cells to irradiation-induced cell death and heating up their immunogenicity. 2575 14


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