Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1261473 (sarcoma)
 25,952 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor growth and the development of metastases are dependent on the local formation of new blood vessels. A major role in the induction of angiogenesis has been assigned to vascular endothelial growth factor (VEGF), a tumor cell-derived endothelium-specific mitogen. We studied whether blood levels of VEGF are increased in sarcoma and carcinoma patients. In addition, we tested whether data from measurements of serum VEGF are of prognostic value with respect to tumor remission during chemotherapy courses of sarcoma patients. First, we measured the concentration of VEGF in the sera of 60 normal volunteers and of 25 untreated patients suffering from solid tumors (13 sarcomas, 12 carcinomas). Second, we studied the level of serum VEGF in 9 tumor patients during 4 courses of ICE-chemotherapy (ifosfamide, carboplatin, etoposide). VEGF was measured by enzyme-linked immunoassay. The concentrations of serum VEGF were significantly higher (P <0.0001) in untreated sarcoma (933+/-132 pg/ml) and carcinoma (1,257+/-169 pg/ml) patients compared to those of normal subjects (239+/-21 pg/ml). The concentration of VEGF was roughly proportional to the tumor mass. A significant fall in serum VEGF occurred in the 6 patients who responded to chemotherapy with tumor remission but not in the patient who were resistant. The concentration of serum VEGF is an indicator of tumor growth in sarcoma and carcinoma patients and thus of prognostic value. Serum VEGF measurements may be clinically useful for monitoring tumor regression in sarcoma patients undergoing chemotherapy.
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PMID:Serum vascular endothelial growth factor (VEGF), a prognostic indicator in sarcoma and carcinoma patients. 2153 81

Soft tissue sarcomas are rare tumours in adults and therefore require a multidisciplinary approach for optimal management. In the metastatic setting, chemotherapy is the primary modality of therapy. Doxorubicin alone or in combination with ifosfamide or dacarbazine has been the backbone of therapy since the 1970s. There is considerable activity for gemcitabine and docetaxel in leiomyosarcoma and for paclitaxel in angiosarcoma. Newer agents such as trabectedin and eribulin may have a role in certain sarcoma subtypes. Palifosfamide may offer a safer alternative to ifosfamide in the future. Many sarcomas have molecular aberrations that can be targeted. Agents that inhibit the insulin-like growth factor receptor-1, mammalian target of rapamycin and vascular endothelial growth factor are currently being investigated.
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PMID:Systemic management strategies for metastatic soft tissue sarcoma. 2203 13

Synovial sarcoma is an obstinate, high-grade malignancy because of its modest responses to radiotherapy and chemotherapy; the identification of effective therapeutics for this sarcoma is therefore necessary. Inhibition of Src family kinases (SFKs) suppresses the proliferation of synovial sarcoma cells in vitro, as we have previously reported. In this study, to validate the efficacy of Src inhibition in vivo, we employed SU6656, which was originally identified as a specific SFK inhibitor. SU6656 treatment significantly impaired the growth of established, existing tumours formed by synovial sarcoma cells in mice. Tumour cell invasion into the surrounding tissues was also abolished by SU6656. It is noteworthy that SU6656 but not PP2 induced a defect in cleavage furrow formation during cytokinesis, resulting in G2/M accumulation and subsequent apoptosis. Intriguingly, SU6656 abrogated the catalytic activities of Aurora kinases and led to the down-regulation of phosphorylated histone H3 coincidently with p53 accumulation, as did the Aurora kinase inhibitor VX-680. Structural comparison indicated an extensive similarity between the catalytic domains of SFKs and Aurora kinases. The structural analysis also revealed the potential binding mode of SU6656 to the ATP-binding cleft of Aurora B via four hydrogen bonds. SU6656 prevented angiogenesis within the tumours by attenuating vascular endothelial growth factor (VEGF) production by tumour cells and the subsequent chemotaxis of endothelial cells; these effects were the result of the inhibition of SFKs but not Aurora kinases. Based on these results, we hereby report a novel property of SU6656 as a dual inhibitor of SFKs and Aurora kinases, the suppression of both of which effectively abrogates tumour development and the progression of synovial sarcoma in vivo.
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PMID:Simultaneous inhibition of Src and Aurora kinases by SU6656 induces therapeutic synergy in human synovial sarcoma growth, invasion and angiogenesis in vivo. 2224 30

Soft tissue sarcomas (STS) are rare mesenchymal cancers with a heterogeneous histology. In terms of oncogenesis, sarcomas may be differentiated into diseases with defined molecular events and sarcomas presenting with complex karyotypes lacking identifiable specific genetic changes or expression profile signatures. The former subtype is amenable to therapy with targeted drugs, especially if the tumor carries a consistent causal mutation occurring early in the disease development. While targeted therapy based on tyrosine kinase inhibition such as imatinib and second generation tyrosine kinase inhibitors plays an important role in the treatment of gastrointestinal stromal tumors (GIST), some progress was also achieved in non-GIST sarcomas. Targeting the PI3 kinase/Akt pathway has been shown to be clinically promising in a diversity of different sarcoma subtypes, and inhibition of the vascular endothelial growth factor (VEGF)/VEGF receptor pathway is of special interest in vascular sarcoma subtypes. MDM2 and p53 seem to be interesting targets for STS, but their role has yet to be defined in further clinical trials. Modification of epigenetic mechanisms, especially deacetylation, might be crucial in other STS subtypes such as translocation-associated entities, but its role has yet to be clinically confirmed. Inclusion of patients in controlled clinical trials combined with a translational research platform is critical for further progress.
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PMID:Targeted therapy of soft tissue sarcomas. 2228 84

Studies on lymph node metastasis of soft tissue sarcomas are insufficient because of its rarity. In this study, we examined the expressions of vascular endothelial growth factor (VEGF)-C and VEGF-D in soft tissue sarcomas metastasized to lymph nodes. In addition, the effects of the two molecules on the barrier function of a lymphatic endothelial cell monolayer against sarcoma cells were analyzed. We examined 7 patients who had soft tissue sarcomas with lymph node metastases and who had undergone neither chemotherapy nor radiotherapy before lymphadenectomy. Immunohistochemistry revealed that 2 of 7 sarcomas that metastasized to lymph nodes expressed VEGF-C both in primary and metastatic lesions. On the other hand, VEGF-D expression was detected in 4 of 7 primary and 7 of 7 metastatic lesions, respectively. Interestingly, 3 cases that showed no VEGF-D expression at primary sites expressed VEGF-D in metastatic lesions. Recombinant VEGF-C at 10(-8) and VEGF-D at 10(-7)and 10(-8)g/ml significantly increased the random motility of lymphatic endothelial cells compared with controls. VEGF-D significantly increased the migration of sarcoma cells through lymphatic endothelial monolayers. The fact that VEGF-D induced the migration of fibrosarcomas through the lymphatic endothelial monolayer is the probable reason for the strong relationship between VEGF-D expression and lymph node metastasis in soft tissue sarcomas. The important propensities of this molecule for the increase of lymph node metastases are not only lymphangiogenesis but also down-regulation of the barrier function of lymphatic endothelial monolayers, which facilitates sarcoma cells entering the lymphatic circulation.
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PMID:Vascular endothelial growth factor-D is a key molecule that enhances lymphatic metastasis of soft tissue sarcomas. 2232 61

Alveolar soft part sarcoma is a rare malignancy usually considered resistant to conventional chemotherapy, but recent data suggest that the multikinase inhibitors sunitinib and cediranib could be active in this setting. A 90-year-old lady with alveolar soft part sarcoma of the leg and lung metastases was started on sunitinib 37.5 mg daily. The treatment was poorly tolerated with grade 3 hypertension and grade 3 thrombocytopenia, which persisted after dose reduction to 25 mg daily. The patient was subsequently started on bevacizumab 10 mg/kg every 2 weeks, resulting in a marked improvement in pain and a partial response on lung metastases for 16 months and ongoing. Agents targeting the vascular endothelial growth factor-signalling pathway seem to exert clinically relevant and prolonged activity against alveolar soft part sarcoma and deserve further evaluation in the treatment of this rare soft tissue sarcoma.
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PMID:Durable clinical activity of single-agent bevacizumab in a nonagenarian patient with metastatic alveolar soft part sarcoma. 2233 Oct 39

Endothelial cell function is critical for angiogenic balance in both physiological and pathological conditions, such as wound healing and cancer, respectively. We report here that soluble heat shock protein beta-1 (HSPB1) is released primarily from endothelial cells (ECs), and plays a key role in regulating angiogenic balance via direct interaction with vascular endothelial growth factor (VEGF). VEGF-mediated phosphorylation of intracellular HSPB1 inhibited the secretion of HSPB1 and their binding activity in ECs. Interestingly, co-culture of tumor ECs with tumor cells decreased HSPB1 secretion from tumor ECs, suggesting that inhibition of HSPB1 secretion allows VEGF to promote angiogenesis. Additionally, neutralization of HSPB1 in a primary mouse sarcoma model promoted tumor growth, indicating the anti-angiogenic role of soluble HSPB1. Overexpression of HSPB1 by HSPB1 adenovirus was sufficient to suppress lung metastases of CT26 colon carcinoma in vivo, while neutralization of HSPB1 promoted in vivo wound healing. While VEGF-induced regulation of angiogenesis has been studied extensively, these findings illustrate the key contribution of HSPB1-VEGF interactions in the balance between physiological and pathological angiogenesis.
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PMID:Soluble HSPB1 regulates VEGF-mediated angiogenesis through their direct interaction. 2235 Jul 94

This work aimed to evaluate serum vascular endothelial growth factor (VEGF) in 25 dogs with soft tissue sarcoma, and in 30 healthy dogs. Blood was collected once time from the control animals and three times, in the same way, from animals with sarcoma. Blood count was performed in the blood collected, and serum VEGF was measured by enzyme-linked immunosorbent assay quantitative method. Serum VEGF in control animals was similar to patients with soft tissue sarcoma. There was a reduction in serum VEGF after the sarcoma resection. There was positive correlation between serum VEGF and neutrophil counts, and negative between VEGF and hemoglobin content in animals with sarcoma. Animals with hemangiopericytoma showed higher serum VEGF levels compared to the patients with malignant peripheral nerve sheath. Circulating blood cells can contribute to elevate VEGF serum concentrations in dogs with soft tissue sarcomas and a possible role of VEGF in the angiogenesis of these tumors.
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PMID:Serum vascular endothelial growth factor in dogs with soft tissue sarcomas. 2237 75

Cutaneous sarcomas are a rare subset of soft tissue sarcomas. These tumors are primarily managed with definitive surgical resection; however, upon unresectable recurrence or metastatic spread, systemic therapy is warranted. As with other sarcomas, these treatments have classically included cytotoxic chemotherapy programs that were associated with variable response rates and poor overall survival. Recently, major advances have been made in the understanding of the molecular biology of these tumors, and treatment paradigms are changing. Multiple pathways have been documented to be important in the growth of cutaneous sarcomas, including receptor tyrosine kinases such as platelet-derived growth factor receptor, insulin-like growth factor receptor and KIT. Dysregulated angiogenesis, through vascular endothelial growth factor (VEGF) and other pathways, is also associated with the growth of these tumors. In this review, we discuss the current standard therapies of cutaneous sarcoma and the recent advances and ongoing investigations into cutaneous sarcoma biology.
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PMID:Advances in the systemic treatment of cutaneous sarcomas. 2248 89

Molecularly targeted agents have shown activity in soft tissue sarcoma (STS) and benign connective tissue tumors over the past ten years, but response rates differ by histologic subtype. The field of molecularly targeted agents in sarcoma is increasingly complex. Often, clinicians must rely on phase II data or even case series due to the rarity of these diseases. In subtypes with a clear role of specific factors in the pathophysiology of disease, such as giant cell tumor of the bone and diffuse-type tenosynovial giant cell tumor, it is reasonable to treat with newer targeted therapies, when available, in place of chemotherapy when systemic treatment is needed to control disease. In diseases without documented implication of a pathway in disease pathogenesis (e.g. soft tissue sarcoma and vascular endothelial growth factor), clear benefit from drug treatment should be established in randomized phase III trials before implementation into routine clinical practice. Histologic subtype will continue to emerge as a critical factor in treatment selection as we learn more about the molecular drivers of tumor growth and survival in different subtypes. Many of the drugs that have been recently developed affect tumor growth more than survival, therefore progression-free survival may be a more clinically relevant intermediate endpoint than objective response rate using Response Evaluation Criteria In Solid Tumors (RECIST) in early phase sarcoma trials. Because of the rarity of disease and increasing need for multidisciplinary management, patients with connective tissue tumors should be evaluated at a center with expertise in these diseases. Participation in clinical trials, when available, is highly encouraged.
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PMID:Histology-specific therapy for advanced soft tissue sarcoma and benign connective tissue tumors. 2261 Mar 42


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