Tyrosine kinase inhibitor SU6668 represses chondrosarcoma growth via antiangiogenesis <Emphasis Type="Italic">in vivo</Emphasis>

Background  

As chondrosarcomas are resistant to chemotherapy and ionizing radiation, therapeutic options are limited. Radical surgery often cannot be performed. Therefore, additional therapies such as antiangiogenesis represent a promising strategy for overcoming limitations in chondrosarcoma therapy. There is strong experimental evidence that SU6668, an inhibitor of the angiogenic tyrosine kinases Flk-1/KDR, PDGFRbeta and FGFR1 can induce growth inhibition of various primary tumors. However, the effectiveness of SU6668 on malignant primary bone tumors such as chondrosarcomas has been rarely investigated. Therefore, the aim of this study was to investigate the effects of SU6668 on chondrosarcoma growth, angiogenesis and microcirculation in vivo.     

Cyclooxygenase-2 blockade can improve efficacy of VEGF-targeting drugs

Anti-angiogenic therapies were approved for different cancers. However, significant primary and secondary resistance hampers efficacy in several tumor types including breast cancer. Thus, we need to develop clinically applicable strategies to enhance efficacy of anti-angiogenic drugs.We report that anti-angiogenic therapies can induce upregulation of cyclooxygenase-2 (Cox-2) and of its product prostaglandin E2 (PGE₂) in breast cancer models. Upon Cox-2 inhibition PGE₂ levels were normalized and efficacy of anti-vascular endothelial growth factor receptor 2 (anti-VEGFR-2) antibodies and sunitinib was enhanced. Interestingly, both treatments exerted additive anti-angiogenic effects. Following Cox-2 inhibition, we observed reduced infiltration of tumors with cancer-associated fibroblasts (CAFs) and lower levels of pro-angiogenic factors active besides the VEGF axis including hepatocyte growth factor (HGF) and basic fibroblast growth factor (FGF2). Mechanistic studies indicated that Cox-2 inhibition reduced PGE₂-induced migration and proliferation of CAFs via inhibiting phosphorylation of Akt.Hence, Cox-2 inhibition can increase efficacy of anti-angiogenic treatments and our findings might pave the road for clinical investigations of concomitant blockade of Cox-2 and VEGF-signaling.     

肝血管生成:在非转移性结肠直肠癌中肿瘤宿主的相互作用(英文)

Objective  

Angiogenesis is a crucial step for tumor growth and progression. Changes of liver angiogenesis (without metastatic invasion) in response to primary tumors are not known. The aim of the study was to investigate the liver angiogenesis in non-metastatic colorectal cancer (CRC).     

Rolle der Strahlentherapie bei strahlensensiblen und strahlenresistenteren Knochentumoren

Background

Radiotherapy plays a pivotal role in multimodal treatment of malignant primary bone tumors. Furthermore it is indicated for analgesic or stabilizing purposes in bone metastases.

Objective

This article gives an overview of the state-of-the-art radiotherapy for malignant primary and secondary bone tumors.

Material and methods

The role of radiotherapy with special reference to modern techniques is demonstrated based on commonly occurring radiosensitive and radioresistant bone tumors.

Results and conclusions

Radiotherapy as monotherapy is of great importance especially for patients with multiple myeloma or bone metastases. The therapy algorithm for Ewing’s sarcoma consists of radiotherapy as part of multimodal treatment, whereas radiotherapy for radioresistant tumors, such as osteosarcoma or chordoma is of little account. Modern techniques, such as intensity modulated radiotherapy (IMRT), imaging-guided radiotherapy (IGRT) or proton therapy now allow administration of high dose radiation for curative treatment of radioresistant tumors.     

Noninvasive treatment of malignant bone tumors using high‐intensity focused ultrasound

BACKGROUND:

High‐intensity focused ultrasound (HIFU) is a new, noninvasive technique with potential to ablate and inactivate tumors. Treatment of solid tumors with HIFU has been reported. In this study, the safety and effects of HIFU in the clinical therapy of malignant bone tumors were assessed.

METHODS:

Biochemical markers and magnetic resonance imaging (MRI) or positron emission tomography (PET)‐computed tomography (CT) were used to evaluate 25 patients with malignant bone tumors before and after HIFU treatment.

RESULTS:

HIFU resulted in significant improvement in biochemical markers, and no severe complications were observed. After HIFU treatment, 21 (87.5%) patients were completely relieved of pain, and 24 (100%) experienced significant relief. On the basis of MRI or PET‐CT, HIFU was effective: For patients with primary bone tumors, 6 (46.2%) had a complete response, 5 (38.4%) had a partial response, 1 (7.8%) had a moderate response, and 1 suffered progressive disease; the response rate was 84.6%. For patients with metastatic bone tumors, 5 (41.7%) had complete response, 4 (33.3%) had partial response, 1 (8.3%) had a moderate response, 1 (8.3%) had stable disease, and 1 suffered progressive disease; the response rate was 75.0%. The 1‐, 2‐, 3‐, and 5‐year survival rates were 100.0%, 84.6%, 69.2%, and 38.5%, respectively, for patients with primary bone tumors and 83.3%, 16.7%, 0%, and 0%, respectively, for patients with metastatic bone tumors. The survival rates for patients with primary bone tumors were significantly better than for those with metastatic tumors.

CONCLUSIONS:

HIFU safely and noninvasively ablated malignant bone tumors and relieved pain. HIFU ablation should be further investigated, as it appears to be successful in the treatment of primary malignant bone tumors. Cancer 2010. © 2010 American Cancer Society.     

Hyperoxia retards growth and induces apoptosis and loss of glands and blood vessels in DMBA-induced rat mammary tumors

Background  

This study investigated the effects of hyperoxic treatment on growth, angiogenesis, apoptosis, general morphology and gene expression in DMBA-induced rat mammary tumors.     

Knochensarkom des Kindes-, Jugend- und jungen Erwachsenenalters

Context

Primary malignant bone tumors are rare and account for only 0.2?% of malignant tumurs. They are, however, more common in children, adolescents and young adults. Osteosarcoma and Ewing’s sarcoma are the most common malignant bone tumors in this age group.

Material and methods

Research of literature and analysis of clinical trials.

Results

Due to modern multimodal treatment, two thirds of patients can be cured if they undergo early and appropriate therapy which requires a precise and early diagnosis made by specialized radiologists and pathologists. Furthermore, treatment in selected medical centers with an interdisciplinary team of specialized oncologists, surgeons and radiotherapists is highly recommended. Nevertheless, clinicians and practitioners whose primary focus is not oncology must be aware of the typical but distinct signs and symptoms of malignant bone tumors, the basic diagnostic procedures and treatment schedules and possible late effects of treatment.     

Effective treatment of diverse medulloblastoma models with mebendazole and its impact on tumor angiogenesis

Background

Medulloblastoma is the most common malignant brain tumor in children. Current standard treatments cure 40%–60% of patients, while the majority of survivors suffer long-term neurological sequelae. The identification of 4 molecular groups of medulloblastoma improved the clinical management with the development of targeted therapies; however, the tumor acquires resistance quickly. Mebendazole (MBZ) has a long safety record as antiparasitic in children and has been recently implicated in inhibition of various tyrosine kinases in vitro. Here, we investigated the efficacy of MBZ in various medulloblastoma subtypes and MBZ''s impact on vascular endothelial growth factor receptor 2 (VEGFR2) and tumor angiogenesis.

Methods

The inhibition of MBZ on VEGFR2 kinase was investigated in an autophosphorylation assay and a cell-free kinase assay. Mice bearing orthotopic PTCH1-mutant medulloblastoma allografts, a group 3 medulloblastoma xenograft, and a PTCH1-mutant medulloblastoma with acquired resistance to the smoothened inhibitor vismodegib were treated with MBZ. The survival benefit and the impact on tumor angiogenesis and VEGFR2 kinase function were analyzed.

Results

We determined that MBZ interferes with VEGFR2 kinase by competing with ATP. MBZ selectively inhibited tumor angiogenesis but not the normal brain vasculatures in orthotopic medulloblastoma models and suppressed VEGFR2 kinase in vivo. MBZ significantly extended the survival of medulloblastoma models derived from different molecular backgrounds.

Conclusion

Our findings support testing of MBZ as a possible low-toxicity therapy for medulloblastomas of various molecular subtypes, including tumors with acquired vismodegib resistance. Its antitumor mechanism may be partially explained by inhibition of tumor angiogenesis.     

In vitro and in vivo inhibitory effect of three Cox-2 inhibitors and epithelial-to-mesenchymal transition in human bladder cancer cell lines

Background:

Although the anti-tumour effect of cyclooxygenase-2 (Cox-2) inhibitors in invasive bladder cancer has been confirmed, its mechanisms of action are unclear. Recently, the concept of an epithelial-to-mesenchymal transition (EMT) promoting carcinoma progression has been suggested, and a key feature of the EMT is the downregulation of E-cadherin. In this study, we investigated the effect of Cox-2 inhibitors on reversal EMT and tumour growth inhibition in bladder cancer cells.

Methods:

We used three Cox-2 inhibitors, etodolac, celecoxib and NS-398 and three human bladder cancer cell lines, T24, 5637 and KK47, in this study. T24 xenograft tumour mouse model was used in the in vivo study.

Results:

Within the clinical drug concentrations, only etodolac showed the in vitro growth inhibition in T24 not in the other cell lines. Etodolac reduced SNAIL mRNA and vimentin cell surface expression, and induced E-cadherin mRNA and E-cadherin cell surface expression, in T24. Etodolac also most strongly inhibited the cell migration of T24 in vitro and showed the highest tumour growth inhibition in T24 tumour in vivo.

Conclusion:

Etodolac at clinical doses exhibited induced in vitro and in vivo anti-tumour effects and reversal effect of EMT in T24. These results suggest that etodolac is a good candidate for an anti-tumour or chemopreventive reagent for high-grade bladder cancer.     

The Src inhibitor dasatinib accelerates the differentiation of human bone marrow-derived mesenchymal stromal cells into osteoblasts

Background  

The proto-oncogene Src is an important non-receptor protein tyrosine kinase involved in signaling pathways that control cell adhesion, growth, migration and differentiation. It negatively regulates osteoblast activity, and, as such, its inhibition is a potential means to prevent bone loss. Dasatinib is a new dual Src/Bcr-Abl tyrosine kinase inhibitor initially developed for the treatment of chronic myeloid leukemia. It has also shown promising results in preclinical studies in various solid tumors. However, its effects on the differentiation of human osteoblasts have never been examined.     

The bone marrow aspirate and biopsy in the diagnosis of unsuspected nonhematologic malignancy: A clinical study of 19 cases

Background  

Although bone marrow metastases can be found commonly in some malignant tumors, diagnosing a nonhematologic malignancy from marrow is not a usual event.     

Peripheral pulmonary nodules: Relationship between multi-slice spiral CT perfusion imaging and tumor angiogenesis and VEGF expression

Background  

The aim of this study is to investigate the relationship between16-slice spiral CT perfusion imaging and tumor angiogenesis and VEGF (vascular endothelial growth factor) expression in patients with benign and malignant pulmonary nodules, and differential diagnosis between benign and malignant pulmonary nodules.     

Endogenous growth inhibition of angiogenesis in brain tumors

The growth inhibition of remote metastases by a primary tumor is known as endogenous growth inhibition leading to tumor dormancy. Such a phenotype has not been described in primary malignant gliomas. However, although glioma cells have frequently spread to other parts of the brain at the time of diagnosis, formation of solid secondary tumors is uncommon. We hypothesize that a dormant population of distant glioma cells exist. The purpose of this study was to investigate whether primary gliomas could inhibit secondary tumor formation. Subcutaneous tumors from human gliomas were grown as xenografts in Swiss nude mice. At a tumor size of at least one cm³, the same amount of cells was injected into the contralateral flank or into the right cerebral hemisphere. Control mice without a primary tumor were injected with tumor cells either into the right flank, the right hemisphere, or bilaterally subcutaneously. Only one of 18 human gliomas demonstrated inhibition at the subcutaneous and intracerebral secondary implantation sites. Growth inhibition of the secondary tumors was accompanied by a significant reduction in microvessel density, upregulation of vascular endothelial growth factor mRNA and downregulation of basic fibroblast growth factor mRNA. Therefore, endogenous inhibition of secondary tumors may represent a rare phenotype in malignant glioma.     

Angiogenesis in cancer of unknown primary: clinicopathological study of CD34, VEGF and TSP-1

Background  

Cancer of unknown primary remains a mallignancy of elusive biology and grim prognosis that lacks effective therapeutic options. We investigated angiogenesis in cancer of unknown primary to expand our knowledge on the biology of these tumors and identify potential therapeutic targets.     

Inhibitory effect of ginsenoside Rg3 combined with gemcitabine on angiogenesis and growth of lung cancer in mice

Background  

Ginsenoside Rg3, a saponin extracted from ginseng, inhibits angiogenesis. The combination of low-dose chemotherapy and anti-angiogenic inhibitors suppresses growth of experimental tumors more effectively than conventional therapy or anti-angiogenic agent alone. The present study was designed to evaluate the efficacy of low-dose gemcitabine combined with ginsenoside Rg3 on angiogenesis and growth of established Lewis lung carcinoma in mice.     

Cimetidine inhibits salivary gland tumor cell adhesion to neural cells and induces apoptosis by blocking NCAM expression

Background  

Cimetidine, a histamine type-2 receptor antagonist, has been reported to inhibit the growth of glandular tumors such as colorectal cancer, however the mechanism of action underlying this effect is unknown. Adenoid cystic carcinoma is well known as a malignant salivary gland tumor which preferentially invades neural tissues. We demonstrated previously that human salivary gland tumor (HSG) cells spontaneously express neural cell adhesion molecule (NCAM), that HSG cell proliferation may be controlled via a homophilic (NCAM-NCAM) binding mechanism and that NCAM may be associated with perineural invasion by malignant salivary gland tumors. We further demonstrated that cimetidine inhibited NCAM expression and induced apoptosis in HSG cells. Here, we investigated the effects of cimetidine on growth and perineural/neural invasion of salivary gland tumor cells.     

Sorafenib (BAY 43-9006) inhibits tumor growth and vascularization and induces tumor apoptosis and hypoxia in RCC xenograft models

Purpose

New research findings have revealed a key role for vascular endothelial growth factor (VEGF) in the stimulation of angiogenesis in clear cell renal carcinoma (RCC) which is a highly vascularized and treatment-resistant tumor. Sorafenib (BAY 43-9006, Nexavar^®) is a multi-kinase inhibitor which targets receptor tyrosine and serine/threonine kinases involved in tumor progression and tumor angiogenesis. The effect of sorafenib on tumor growth and tumor histology was assessed in both ectopic and orthotopic mouse models of RCC.

Methods

Sorafenib was administered orally to mice bearing subcutaneous (SC, ectopic) or sub-renal capsule (SRC, orthotopic) tumors of murine (Renca) or human (786-O) RCC. Treatment efficacy was determined by measurements of tumor volume and tumor growth delay. In mechanism of action studies, using the 786-O and Renca RCC tumor models, the effect of sorafenib was assessed after dosing for 3 or 5 days in the SC models and 21 days in the SRC models. Inhibition of tumor angiogenesis was assessed by measuring level of CD31 and α-smooth muscle actin (αSMA) staining by immunohistochemistry (IHC). The effect of sorafenib on MAPK signaling, cell cycle progression and cell proliferation was also assessed by IHC by measuring levels of phospho-ERK, phospho-histone H3 and Ki-67 staining, respectively. The extent of tumor apoptosis was measured by terminal deoxynucleotidyl transferase-mediated nick-end labeling (TUNEL) assays. Finally, the effects of sorafenib on tumor hypoxia was assessed in 786-O SC model by injecting mice intravenously with pimonidazole hydrochloride 1 h before tumor collection and tumor sections were stained with a FITC-conjugated Hypoxyprobe antibody.

Results

Sorafenib produced significant tumor growth inhibition (TGI) and a reduction in tumor vasculature of both ectopic and orthotopic Renca and 786-O tumors, at a dose as low as 15 mg/kg when administered daily. Inhibition of tumor vasculature was observed as early as 3 days post-treatment, and this inhibition of angiogenesis correlated with increased level of tumor apoptosis (TUNEL-positive) and central necrosis. Consistent with these results, a significant increase in tumor hypoxia was also observed 3 days post-treatment in 786-O SC model. However, no significant effect of sorafenib on phospho-ERK, phospho-histone H3 or Ki-67 levels in either RCC tumor model was observed.

Conclusion

Our results show the ability of sorafenib to potently inhibit the growth of both ectopically- and orthotopically-implanted Renca and 786-O tumors. The observed tumor growth inhibition and tumor stasis or stabilization correlated strongly with decreased tumor angiogenesis, which was due, at least in part, to inhibition of VEGF and PDGF-mediated endothelial cell and pericyte survival. Finally, sorafenib-mediated inhibition of tumor growth and angiogenesis occurred at concentrations equivalent to those achieved in patients in the clinic.     

Expression of p53, inducible nitric oxide synthase and vascular endothelial growth factor in gastric precancerous and cancerous lesions: correlation with clinical features

Background  

The growth and metastasis of tumors depend on the development of an adequate blood supply via angiogenesis. Recent studies indicate that the inducible nitric oxide synthase (iNOS), vascular endothelial growth factor (VEGF) and the tumor suppressor p53 are fundamental play-markers of the angiogenic process. Overexpression of iNOS and VEGF has been shown to induce angiogenesis in tumors. P53 suppresses angiogenesis by down-regulating VEGF and iNOS. The correlation of expression of p53, VEGF and iNOS and clinical features in gastric carcinogenesis, however, has not been well characterized.