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)

This manuscript reviews the theories behind the propensity of prostate cancer to cause bone metastases and skeletal implications of the prostate cancer biology and treatment modalities. The escape of tumor cells from the primary tumor in the prostate to secondary tumor sites in the axial skeleton probably occurs before the primary tumor is detected. Several theories offer explanations for the observed proclivity of prostate tumors to selectively colonize the axial skeleton. The interaction between the tumor cells and cells that populate bone marrow, in particular osteoblasts and osteoclasts, is important for creating a 'fertile' environment where tumor cells can establish and grow. Prostate cancer cells are capable of producing growth factors that can affect both osteoblasts, resulting in osteoblastic bone formation, and osteoclasts, resulting in excessive bone resorption. In addition to the capability to progress from testosterone-dependent to testosterone-independent phenotype, the hallmark of metastatic prostate cancer is osteosclerosis similar to one induced experimentally in nude rats using CWR22 human prostate cancer cell line. Metastatic bone disease caused by excessive bone formation and bone resorption is the major cause of morbidity in patients with prostate cancer. The most common symptoms include pain, pathological fractures, spinal cord compression, cranial nerve palsies, bone marrow suppression and hypercalcemia. The introduction of prostate-specific antigen in clinical practice created a shift to where more prostate cancer patients with early disease receive androgen ablation treatment, which in return causes more bone loss and cancer-associated osteoporosis. Introduction of third generation bisphosphonates to treat skeletal consequences of malignancy further stressed the important interaction between the bone marrow stroma and cancer cells. Nevertheless, animal models and human prostate tumor cell lines that mimic all aspects of skeletal conditions in prostate cancer patients including osteoblastic bone response are needed to develop and screen for novel therapeutic and diagnostic modalities.
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PMID:Skeletal implications of prostate cancer. 1575 51

Gene modification of tumor cells is commonly utilized in various strategies of immunotherapy preventive both as treatment and a means to modify tumor growth. Gene transfer prior to surgery as neoadjuvant therapy has not been studied systematically. We addressed, whether direct intra-tumoral injection of a recombinant adenovirus expressing the immunomodulatory molecule, heat shock protein 72 (ADHSP72), administered prior to surgery could result in sustainable anti-tumor immune responses capable of affecting tumor progression and survival in a number of different murine and rat tumor models. Using intra-dermal murine models of melanoma (B16), colorectal carcinoma (CT26), prostate cancer (TrampC2) and a rat model of glioblastoma (9L), tumors were treated with vehicle or GFP expressing adenovirus (ADGFP) or ADHSP72. Tumors were surgically excised after 72 h. Approximately 25-50% of animals in the ADHSP72 treatment group but not in control groups showed sustained resistance to subsequent tumor challenge. Tumor resistance was associated with development of anti-tumor cellular immune responses. Efficacy of ADHSP72 as neoadjuvant therapy was dependent on the size of the initial tumor with greater likelihood of immune response generation and tumor resistance associated with smaller tumor size at initial treatment. ADHSP72 neoadjuvant therapy resulted in prolonged survival of animals upon re-challenge with autologous tumor cells compared to ADGFP or vehicle control groups. To study the effects on tumor progression of distant metastases, a single tumor focus of animals with multifocal intra-dermal tumors was treated. ADHSP72 diminished progression of the secondary tumor focus and prolonged survival, but only when the secondary tumor focus was <50 mm3 . Our results indicate that gene modification of tumors prior to surgical intervention may be beneficial to prevent recurrence in specific circumstances.
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PMID:Anti-tumor immune responses following neoadjuvant immunotherapy with a recombinant adenovirus expressing HSP72 to rodent tumors. 1588 53

The rationale for locoregional staging lymphadenectomy in prostate cancer lies in the accurate diagnosis of occult micrometastases in order to stratify patients who might benefit from adjuvant therapeutic measures. In prostate cancer, extended pelvic lymphadenectomy (EPLA) including the lymphatic tissue along the common iliac region with the ureteral crossing as cranial margin, external and internal iliac region and the obturator fossa, has been shown to increase the yield of both total lymph nodes and lymph node metastases significantly. The total number of lymph nodes removed is about 2- to 3-fold higher and the frequency of micrometastatic lymph nodes is approximately 2-fold higher compared to standard lymphadenectomy. Furthermore, the frequency of observed positive lymph nodes in clinically localized and locally advanced prostate cancer is significantly higher than predicted by nomograms such as Partin tables and CART analysis. Although there are no prospective randomized trials demonstrating a survival benefit associated with EPLA, there might be an advantage for those with minimal lymph node involvement. Progression-free survival is significantly improved in patients undergoing EPLA with a 35 % benefit compared to standard lymphadenectomy. Various studies have documented an equal risk of cancer-associated mortality in patients with no or only 1 - 2 positive lymph nodes. Since the surgery-associated morbidity of EPLA is not increased as compared to standard lymphadenectomy, EPLA should be favoured at least for all intermediate and high risk patients undergoing radical prostatectomy; in low risk patients the option of EPLA has to be discussed thoroughly. For the future, ongoing prospective trials have to demonstrate a clear benefit in terms of biochemical-free and cancer-specific survival. With regard to muscle-invasive bladder cancer, it has been shown that lymph node dissection along the external, internal and common iliac artery and obturator fossa achieves accurate data for a valid locoregional staging. Only if frozen section analysis reveals metastatic deposits along these areas an extension of the lymphadenectomy including the aortic bifurcation up to the inferior mesenteric artery seems to be of additional diagnostic value. Various studies have demonstrated that extended pelvic lymphadenectomy results in an improvement of progression-free survival, however no significant benefit with regard to cancer-specific and overall survival has been demonstrated. Nevertheless, pelvic lymphadenectomy remains one of the most significant prognosticators with regard to relapse rates as has been demonstrated recently and, therefore, it should be performed thoroughly and anatomically adequate.
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PMID:[The role of pelvic lymphadenectomy in the therapy of prostate and bladder cancer]. 1600 37

Growth of solid tumor metastases is critically dependent on angiogenesis. We hypothesized that an "angiogenic-rich" milieu, as in pneumonectomy-induced lung growth, would be conducive to growth of pulmonary metastases, and that transfer of an antiangiogenic gene would suppress tumor growth. Two weeks after left pneumonectomy in BALB/c mice, right lung mass increased 1.5-fold compared with controls (P < 0.0001). Our pulmonary metastases model, intravenous administration of beta-galactosidase (betagal)-marked CT26.CL25 colon carcinoma cells, resulted in diffuse metastases at 12 d after administration. However, if left pneumonectomy was performed 1 d before tumor cell administration, right lung mass was increased 1.7-fold after 12 d (P < 0.001 compared with the right + left lung of controls), and betagal activity was greater (2.8-fold, P < 0.05). To assess antiangiogenesis therapy, tumor cells were administered 1 d after pneumonectomy and 1 d later, 5 x 10(8) plaque-forming units of Adsflt (an Ad vector expressing the extracellular portion of the flt-1 vascular endothelial growth factor [VEGF] receptor) was administered. Compared with controls, mice receiving Adsflt via intranasal or intravenous routes showed suppression of pneumonectomy-induced tumor growth (P < 0.01, both routes compared with controls). Postpneumonectomy lung growth enhances growth of lung metastases, but this can be suppressed with Adsflt antiangiogenesis therapy.
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PMID:Gene transfer of the vascular endothelial growth factor receptor flt-1 suppresses pulmonary metastasis associated with lung growth. 1615 Oct 52

Alterations in bone architecture and mineral metabolism are common complications of malignancy. Cancers such as breast, prostate, and lung can affect the skeleton either indirectly through the elaboration of factors that act to disrupt normal calcium homeostasis at the level of the kidney and bone; or directly via secondary spread of tumor to bone. Although the pathophysiology of these skeletal complications is diverse, it is clear that the osteoclast and osteoblast are not just bystanders but are active participants in the development and progression of hypercalcemia and bone metastasis. Our understanding of the molecular mechanisms of metastasis leading to tumor cell escape, homing, adhesion, and secondary growth in a hospitable environment are evolving. Treatment modalities aimed at not only reducing tumor burden but altering the skeletal response to tumor have shown benefit. Newer generation bisphosphonates are quite effective in controlling hypercalcemia of malignancy and have been shown to delay progression of skeletal metastases. Clearly, cancer-associated bone morbidity remains a major public health problem. To improve therapy and prevention it is important to understand the pathophysiology of the effects of cancer on bone. This review will detail scientific advances regarding this area.
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PMID:Mechanisms and treatment for bone metastases. 1616 96

Some markers of angiogenic endothelial cells are emerging as targets of cancer therapy. The present study compares the expression of CD105 with that of other endothelial markers in all tissue layers during the development of colon cancer. We immunohistochemically analyzed the expression of the colon adenoma-carcinoma sequence by endothelial cells using a panel of eight endothelial markers. We examined sections from endoscopic mucosal resection and surgical resection of tubular adenoma (n=31), carcinoma in adenoma (n=11), and adenocarcinoma (n=34). Cylindrical cores were punched out from donor paraffin blocks of normal mucosa adjacent to tumors, from tumor lesions of mucosa, submucosa, muscularis propria, subserosa, and serosa, and from lymph node metastases. CD31 (PECAM-1) was universally expressed in the blood vessels of adenoma-carcinoma lesions as well as in normal mucosal vessels (80-95%), with no significant differences. In contrast, cancer-associated blood vessels (up to 80%) and cancer cells themselves expressed high levels of CD105. In normal mucosa, CD105 was weakly expressed in endothelial cells of capillaries (< or =21%), and significant differences in its expression in endothelial cells between the normal mucosa and adenoma, carcinoma in adenoma, and adenocarcinoma were found. Flt-1, Flk-1, transforming growth factor-beta1, transforming growth factor-beta receptor II, and CD44 were strongly expressed in the cancer cells but were not expressed in the blood vessels. Vascular endothelial growth factor was expressed at <30% in the blood vessels of adenoma, carcinoma in adenoma, and carcinoma. Moreover, this study provided evidence that CD105 was expressed exclusively in endothelial blood vessels by double immunostaining of CD105 and D2-40. The present study shows that de novo blood vessels of colon cancer specifically express CD105. These findings provide the basis for novel antiangiogenic cancer therapies.
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PMID:Endoglin (CD105) expression in angiogenesis of colon cancer: analysis using tissue microarrays and comparison with other endothelial markers. 1617 81

Pancreatic adenocarcinoma (PC) is an aggressive malignancy resistant to standard treatment modalities. Previously, we have reported that cancer-associated Sm-like protein (CaSm) contributes to the neoplastic transformation of PC. In this study, we utilized a recently established preclinical model of PC to determine if molecular targeting of CaSm can serve as the basis for a novel PC therapy. In a subcutaneous tumor model, intratumoral administration of an adenoviral vector encoding CaSm antisense RNA (Ad-alphaCaSm) significantly inhibited Panc02 tumor growth. Furthermore, in a metastatic tumor model, systemic administration of Ad-alphaCaSm resulted in a significant decrease in the number of hepatic metastases and increased survival time. We assessed the efficiency of in vivo delivery and observed significant levels of vector transduction in tissues containing PC, as well as a bystander effect that was amplifying the efficacy of CaSm gene therapy. This bystander effect was also active in vitro and was shown to be at least partially independent of host-related mechanisms. We conclude that CaSm antisense gene therapy is an effective novel therapy for PC and that the antitumor efficacy is dependent on both direct and bystander mechanisms.
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PMID:Bystander effect contributes to the antitumor efficacy of CaSm antisense gene therapy in a preclinical model of advanced pancreatic cancer. 1622 92

Angiogenesis is essential for solid tumor growth. Although successful antiangiogenic therapies have been demonstrated in animal models, a systematic comparison of the efficacy of different antiangiogenic factors has not been described in the hepatic environment. To address this issue, CT26 murine colon carcinoma cells were transfected with retroviral vectors encoding murine endostatin (mEndostatin), human angiostatin (hAngiostatin), murine-soluble vascular endothelial growth factor receptor-2, (msFlk-1), or murine-soluble Tie2 (msTie2). The transfected cells were then subjected to another round of transfection with a luciferase cDNA-encoding retroviral vector. Expression of these putative antiangiogenic proteins inhibited the proliferation of human umbilical vein endothelial cells in vitro but not tumor cells. To examine effects on tumor growth in vivo, modified cells were delivered via intrasplenic injection into BALB/c mice to induce liver metastases. Tumor burden was measured weekly by bioluminescence. Growth of hepatic metastases in vivo was significantly reduced in mice that were administered cells expressing msTie2 (76% reduction compared with control cells 21 days after intrasplenic inoculation; P < 0.05). Similar results were observed with cells that expressed msFlk-1 and hAngiostatin. However, expression of mEndostatin had no significant effect on the growth of liver metastases compared with control animals. These findings indicate that multiple antiangiogenic pathways are necessary for the growth of hepatic metastases, and each of these pathways is a potential clinically relevant antiangiogenic target for the treatment of this disease.
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PMID:A comparison of antiangiogenic therapies for the prevention of liver metastases. 1624 20

Cancer is frequently complicated by thrombosis, which may even be the first sign of an unrecognized cancer. There are several risk factors for cancer-associated thrombosis, such as type of malignancy, the presence of metastatic disease, and the use of chemotherapy. In most patients with cancer, a procoagulant state can be identified, ranging from subclinical laboratory abnormalities to full-blown disseminated intravascular coagulation. A specific entity is the occurrence of thrombotic microangiopathy that is specifically related to (high-dose) chemotherapy and radiotherapy. The pathogenetic pathways that play a role in the cancer-associated coagulopathy have been identified in recent years.
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PMID:Cancer and thrombosis. 1625 68

Interaction of nuclear beta-catenin and TCF4 is the end point of canonical Wnt signaling, which is believed to trigger the transcription of multiple cancer-associated genes, including CD44. So far, the combined status of beta-catenin and TCF4 and its relevance for lymph node metastasis and CD44 expression have not been well studied in gastric cancers (GCs). To address these issues, we examined 31 GCs, 17 premalignant tissues, 10 noncancerous gastric mucosae, 17 regional lymph node metastases, and 4 human GC cell lines (MGC803, MGC823, AGS, and HGC-27) using immunohistochemical and immunofluorescence staining, reverse transcriptase polymerase chain reaction, and Western blot analysis. Frequent TCF4 up-regulation and nuclear translocation of beta-catenin were found in both primary and metastatic tumors. Standard CD44 was detected in all gastric tissue samples. The frequency of variant CD44 expression increased in parallel with stepwise gastrocarcinogenesis and tumor spread, but the rates of detection did not match that of nuclear beta-catenin and TCF4, especially in the premalignant and noncancerous samples. The data from the 4 cell lines were in accordance with the in vivo findings in terms of beta-catenin nuclear translocation, TCF4 activation, and CD44 expression. Our results suggest an established Wnt signaling pathway in most GCs, a close correlation of beta-catenin/TCF4-mediated signaling with tumor dissemination, and the unlikelihood of a direct effect of activated Wnt signaling on CD44 expression. The influence of beta-catenin-TCF4 interaction on alternative CD44 splicing was not established. These 3 alterations may be regarded as unfavorable features of GC.
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PMID:Nuclear translocations of beta-catenin and TCF4 in gastric cancers correlate with lymph node metastasis but probably not with CD44 expression. 1631 Nov 23


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