Phosphorylated KDR expression in endometrial cancer cells relates to HIF1alpha/VEGF pathway and unfavourable prognosis.

Vascular endothelial growth factor (VEGF) is a potent angiogenic factor for many malignant neoplasms exerting its function through activation of specific membrane receptors, that is, KDR/flk-1, residing in endothelial cells. Several recent reports indicate that VEGF receptors are also expressed in cancer cells, suggesting that specific VEGF-originated cancer cell reactions may parallel the endothelial response. Using a novel monoclonal antibody, recognizing the activated (phosphorylated) form of the KDR receptor (pKDR), we assessed the expression of pKDR in normal and malignant endometrium.

Hypoxia-inducible factor-2 alpha (HIF-2 alpha) induces angiogenesis in breast carcinomas.

Hypoxia-inducible factors-1alpha (HIF-lalpha) and HIF-2alpha are important proteins initiating tumor cell responses to hypoxia. Specifically, the transcription of genes related to erythropoiesis, glycolysis, and angiogenesis depends on the rate of HIFalpha binding to DNA at the hypoxia response elements of target genes. In this study, the authors evaluated the immunohistochemical expression of HIF-2alpha in 62 infiltrating ductal carcinomas of the breast, not otherwise specified, in relation to estrogen and progesterone receptors, the MIB1 proliferation index, the vascular density, and the proteins c-erbB-2, bcl-2, and p53.

Comparison of metabolic pathways between cancer cells and stromal cells in colorectal carcinomas: a metabolic survival role for tumor-associated stroma.

Understanding tumor metabolism is important for the development of anticancer therapies. Immunohistochemical evaluation of colorectal adenocarcinomas showed that cancer cells share common enzyme/transporter activities suggestive of an anaerobic metabolism [high lactate dehydrogenase 5 (LDH5)/hypoxia-inducible factor alphas (HIFalphas)] with high ability for glucose absorption and lactate extrusion [high glucose transporter 1 (GLUT1)/monocarboxylate transporter (MCT1)]. The tumor-associated fibroblasts expressed proteins involved in lactate absorption (high MCT1/MCT2), lactate oxidation (high LDH1 and low HIFalphas/LDH5), and reduced glucose absorption (low GLUT1).

Endogenous markers of two separate hypoxia response pathways (hypoxia inducible factor 2 alpha and carbonic anhydrase 9) are associated with radiotherapy failure in head and neck cancer patients recruited in the CHART randomized trial.

Purpose: Randomized controlled trials have generally shown a benefit from accelerated radiotherapy in head and neck squamous cell carcinoma (HNSCC). However, the large randomized United Kingdom trial CHART (Continuous Hyperfractionated Accelerated Radiotherapy) failed to show a benefit of strongly accelerated over standard radiotherapy (RT) in 918 patients with HNSCC. In this study, we investigated the impact of tumor hypoxia on the outcome of HNSCC patients in the CHART trial.

Angiogenic effect of intramuscular administration of basic and acidic fibroblast growth factor on skeletal muscles and influence of exercise on muscle angiogenesis.

Background: Angiogenic factors which control the angiogenic process represent a promising strategy for restoration of blood flow, but require further evaluation before clinical use. Exercise has also been reported to induce neovascularisation in muscles.

Objectives: To evaluate the angiogenic effects of basic fibroblast growth factor (b-FGF) and acidic fibroblast growth factor (a-FGF) on rat gastrocnemius muscle, when administered intramuscularly, and to compare them with those obtained by daily exercise.

Inclusion of vasculature-related variables in the Dukes staging system of colon cancer.

Purpose: The Dukes stage is used to stratify colorectal cancer patients into groups of different prognosis and need of adjuvant radiotherapy and chemotherapy. However, approximately 80% of patients with Dukes stage C colorectal cancer receive cytotoxic therapy without any expected benefit, for such patients would either not relapse without adjuvant therapy or they would inevitably do so because of tumor resistance to the available regimens. On the other hand, as 20% of Dukes stage B patients would relapse after surgery, adjuvant therapy could improve their survival.

Loss of expression and nuclear/cytoplasmic localization of the FOXP1 forkhead transcription factor are common events in early endometrial cancer: relationship with estrogen receptors and HIF-1alpha expression.

The FOXP1 gene has been identified as a new member of the winged helix family of transcription factors that have important roles in cellular transformation, differentiation and proliferation. In this study, we examined the expression of FOXP1 in the normal and malignant endometrium (stage I endometrioid adenocarcinoma cases), showing a frequent deregulation of its expression in cancer. Proliferative endometrium showed predominantly nuclear localization of FOXP1, while exclusively weak cytoplasmic staining was present in the secretory phase.

Hypofractionated accelerated radiotherapy with cytoprotection combined with trastuzumab, liposomal doxorubicine, and docetaxel in c-erbB-2-positive breast cancer.

Objectives: Trastuzumab, an antic-erbB-2 monoclonal antibody, has become a standard component of chemotherapy for c-erbB-2-positive advanced breast carcinoma. Despite the experimental evidence of its radiosensitizing properties, trastuzumab has never been used in combination with radiotherapy for the treatment of patients with locally advanced disease.

Patients And Methods: Twenty-two patients with c-erbB-2-positive locally advanced chemoresistant (7 patients) or with high-risk breast cancer (15 patients) were recruited in a treatment protocol combining hypofractionated/accelerated radiotherapy (hypoARC) supported with high-dose amifostine (1000 mg subcutaneous), concurrently with trastuzumab (4 mg/kg every 2 weeks).

Proliferating fibroblasts at the invading tumour edge of colorectal adenocarcinomas are associated with endogenous markers of hypoxia, acidity, and oxidative stress.

Background: Stroma frequently forms at sites of active tumour invasion, and may be important for tumour growth and progression. The term "stromatogenesis" is used to describe this unique process that involves host peritumorous fibroblasts and is very different to reactive fibrosis.

Aims/methods: To investigate the activation status of host fibroblasts at the invading tumour edge, assessed as MIB1 proliferation index and thymidine phosphorylase (TP) expression.

Node-related factors and survival in node-positive breast carcinomas.

The number of positive lymph nodes (+LNs) is the only node-related prognostic factor recognized by the American Joint Committee TNM system for breast cancer. In this study, we evaluated additional node-related prognostic factors in node-positive breast carcinomas. One hundred and thirty-four patients with infiltrating ductal carcinomas and axillary +LNs, who had been treated with modified radical mastectomy, were analyzed.

Lactate dehydrogenase 5 (LDH5) relates to up-regulated hypoxia inducible factor pathway and metastasis in colorectal cancer.

Lactate dehydrogenase 5 (LDH5) is one of the five LDH isoenzymes and, apparently, the most important for promoting anaerobic glycolysis. LDH5 is transcriptionally regulated by the hypoxia inducible factors (HIF) 1alpha and 2alpha. In this study, the possible aggressive advantages that colorectal tumours may gain from a high LDH5 content was investigated.

The HIF-2alpha/VEGF pathway activation in cutaneous capillary haemangiomas.

Aim: To investigate the pathogenesis of capillary haemangiomas, a common form of vascular malformation.

Methods: Twenty-five cutaneous capillary haemangiomas, excised from patients under 14 years of age, were studied immunohistochemically for endothelial cells, the angiogenic factors thymidine phosphorylase (TP) and vascular endothelial growth factor (VEGF), the proliferation index Ki-67, and the hypoxia inducible factors-1alpha (HIF-1alpha) and -2alpha (HIF-2alpha).

Results: Endothelial-lined channels reacted strongly with CD31 in all cases, clearly definining capillary spaces.

Thymidine phosphorylase expression in patients with chronic viral hepatitis.

Background: The role of thymidine phosphorylase (TP), an angiogenic factor, in chronic viral hepatitis is unclear. In the present study we investigated TP expression in chronic viral hepatitis due to hepatitis B virus (HBV) and hepatitis C virus (HCV) infection.

Methodology: Fifty-eight patients suffering from chronic viral hepatitis and 13 cirrhotic patients due to either HBV or HCV were studied.

Pyruvate dehydrogenase and pyruvate dehydrogenase kinase expression in non small cell lung cancer and tumor-associated stroma.

Pyruvate dehydrogenase (PDH) catalyzes the conversion of pyruvate to acetyl-coenzyme A, which enters into the Krebs cycle, providing adenosine triphosphate (ATP) to the cell. PDH activity is under the control of pyruvate dehydrogenase kinases (PDKs). Under hypoxic conditions, conversion of pyruvate to lactate occurs, a reaction catalyzed by lactate dehydrogenase 5 (LDH5).

Comparison of angiogenic activities after urethral reconstruction using free grafts in rabbits.

Objective: To determine the most suitable type of graft-free penile skin grafts or mucosal grafts from bladder or buccal regions - for urethral reconstruction in an animal model, as evaluated on the basis of angiogenic activity.

Methods: Twenty-two male White New Zealand rabbits were randomly divided into four groups. In the control group (group O, n=4) a simple urethrotomy and closure was performed, whereas a ventral urethral defect was created in groups A, B, and C and then bridged using the following onlay patches: free penile skin (group A, n=6), buccal mucosal graft (group B, n=6), and bladder mucosal graft (group C, n=6).

LYVE-1 immunohistochemical assessment of lymphangiogenesis in endometrial and lung cancer.

Aims/methods: Normal and malignant pulmonary and endometrial tissues were analysed for lymphatic vessels to assess the process of lymphangiogenesis and its role at these sites, using specific immunostaining for LYVE-1 and the panendothelial marker CD31.

Results: Lymphatics were clearly demonstrated in some normal tissues (myometrium, bronchial submucosa, and intestinal submucosa), but not in others (endometrium and alveolar tissue). LYVE-1 positive lymphatic vessels were detected at the tumour periphery of endometrial and lung carcinomas, but not within the main tumour mass.

The angiogenetic effect of intramuscular administration of VEGF on muscle. The influence of exercise on angiogenesis.

Unlabelled: Although angiogenetic therapy using recombinant growth factors holds much hope for the treatment of ischemic diseases, there are still unanswered questions including the method, doses or duration of therapeutic approach. We evaluated the angiogenetic effects of vascular endothelial growth factor (VEGF) on rat heart and gastrocnemius muscles when this was administered intramuscularly and compared them to those obtained from rats, which exercised daily.

Conclusion: Both daily swimming exercise and intramuscular administration of VEGF increased angiogenesis in rat heart, even though exercise alone was the only one that increased angiogenesis quite significantly.

Impact of hiatal hernia on histological pattern of non-erosive reflux disease.

Background: Hiatus hernia (HH) has major pathophysiological effects favoring gastroesophageal reflux and hence contributing to esophageal mucosa injury, especially in patients with severe gastroesophageal disease. However, prospective studies investigating the impact of HH on the esophageal mucosa in non-erosive reflux disease (NERD) are lacking. This study evaluated the association between the presence of (HH) and the histological findings in symptomatic patients with NERD.

c-erbB-2 related aggressiveness in breast cancer is hypoxia inducible factor-1alpha dependent.

c-erbB-2-positive breast carcinomas are highly aggressive tumors. In vitro data on breast cell lines showed that c-erbB-2 enhanced translational efficiency of hypoxia inducible factor-1alpha (HIF1alpha) production (Laughner et al., Mol Cell Biol 2001;21:3995-4005).

Tumour angiogenesis: vascular growth and survival.

Angiogenesis starts at the edge of a malignant epithelial tumour concurrently with tumour cell invasion and stromatogenesis, i.e. the formation of specific connective tissue stroma amenable to easy penetration by endothelial and tumour cells.

VEGF gene sequence variation defines VEGF gene expression status and angiogenic activity in non-small cell lung cancer.

Different vascular endothelial growth factor (VEGF) gene polymorphisms have been shown to result in different VEGF gene responsiveness to various stimuli and different capacity for VEGF protein production. In the present study, we examined four VEGF gene polymorphisms in thirty-six individuals with non-small cell lung cancer (NSCLC). Gene polymorphisms were correlated with the VEGF protein expression in cancer cells and the tumor angiogenic activity.

Angiogenesis and vascular survival ability in ovarian adenocarcinomas.

This study was designed to investigate the prognostic relevance of ovarian tumour angiogenesis in terms of tumour angiogenic activity (TAA) and vascular survival ability (VSA), i.e. the ability of newly formed vessels to survive once incorporated into the main tumour mass.

BNIP3 expression is linked with hypoxia-regulated protein expression and with poor prognosis in non-small cell lung cancer.

BNIP3 is a proapoptotic protein regulated by hypoxia-inducible factor 1. We analyzed BNIP3 expression in 105 tumor samples from early operable, non-small lung cancer and the relationship of expression to hypoxia-inducible factor 1alpha, other hypoxia-regulated pathways, and prognosis. There was strong cytoplasmic expression in >10% of cells in 40 of 105 cases.