Function and mutual interaction of BiP-, PERK-, and IRE1α-dependent signalling pathways in vascular tumours.

Spontaneously regressing infantile haemangiomas and aggressive angiosarcomas are vascular tumours with excessive angiogenesis. When analysing haemangiomas and angiosarcomas immunohistochemically with respect to their chaperone profiles we found that angiosarcomas have significantly elevated protein levels of binding immunoglobulin protein (BIP) and PERK with concomitant attenuated IRE1α levels, whereas haemangioma tissue exhibits the same pattern as embryonal skin tissue. We show that BiP is essential for the maintenance of VEGFR2 protein, which is expressed in the endothelium of both tumour types.

The relevance of cell type- and tumor zone-specific VEGFR-2 activation in locally advanced colon cancer.

Background: For the successful therapeutic use of inhibitors of the vascular endothelial growth factor receptor (VEGFR) pathway detailed knowledge of the mechanisms leading to tumor progression is indispensable. The main goal of this study was to determine the relevance of the VEGFR-2 activating pathway for colon carcinoma (CC) metastasis. The initial event is ligand-induced receptor activation through tyrosine autophosphorylation.

Cell type- and tumor zone-specific expression of pVEGFR-1 and its ligands influence colon cancer metastasis.

Background: Detailed knowledge of the essential pro-angiogenic biomolecules, the vascular endothelial growth factor (VEGF) family and its receptors, in the characteristically heterogeneous tumor tissue is a pre-requisite for an effective personalized target therapy. The effects of VEGF receptors after ligand binding are mediated through receptor tyrosine autophosphorylation. We determined the relevance of the VEGFR-1 activating pathway for colon cancer (CC) metastasis.

Histopathological features predict metastatic potential in locally advanced colon carcinomas.

Background: Metastatic dissemination can exist before a pathologically and clinically detectable manifestation. The structural heterogeneity of colon cancer (CC) in histological sections with respect to the morphology of tumor aggressiveness and composition of the tumor microenvironment raises the question of whether the microscopical tumor architecture enables a discrimination of groups with different metastatic potential. This would result in an assessment of the prognosis and provision of an ancillary tool for the therapeutic management after surgery, beside the estimation of the local tumor extent.

VEGF-B expression in colorectal carcinomas and its relevance for tumor progression.

The biological behavior of VEGF-B, a ligand of the receptor VEGFR-1, is still enigmatic. Despite its high sequence homology to the better known angiogenetic factor VEGF-A, the function of VEGF-B has remained elusive. Especially, its role in tumor biology has thus far not been defined.

Pulmonary histiocytic sarcoma mimicking pulmonary Langerhans cell histiocytosis in a young adult presenting with spontaneous pneumothorax: a potential diagnostic pitfall.

We present a case of a histiocytic sarcoma incidentally detected in peripheral lung tissue resected for a spontaneous pneumothorax. Furthermore, we discuss the practical approach to pulmonary Langerhans cell histiocytosis, the main differential diagnosis of this lesion in the lung, based on morphological and immunohistochemical features. A 23-year-old male patient presented with recurrent pneumothoraces.

Comparative study of human colonic tumor-derived endothelial cells (HCTEC) and normal colonic microvascular endothelial cells (HCMEC): Hypoxia-induced sVEGFR-1 and sVEGFR-2 levels.

Colorectal carcinoma growth and progression is dependent on the vasculature of the tumor microenvironment. Tumor-derived endothelial cells differ functionally from their normal counterpart. For this reason we isolated microvascular endothelial cells from human colon cancer tissue (HCTEC) and compared them with endothelial cells from normal colonic tissue (HCMEC) of the same donor.

Hypoxia-induced reduction of sVEGFR-2 levels in human colonic microvascular endothelial cells in vitro: Comparative study with HUVEC.

The functionality of large-vessel endothelial cells, such as human umbilical vein endothelial cells (HUVEC), may differ significantly from that in the microvasculature. We established a method for the isolation of human colonic microvascular endothelial cells (HCMEC). Since colonic diseases are often accompanied by hypoxia we examined its effects on HCMEC of five individuals in comparison with HUVEC, with respect to the secretion of the soluble form of the two important vascular endothelial growth factor (VEGF) receptors, VEGFR-1 and 2.

Hypoxia-inducible factor 1 alpha expression increases during colorectal carcinogenesis and tumor progression.

Background: Hypoxia-inducible factor 1 alpha (HIF-1alpha) is involved in processes promoting carcinogenesis of many tumors. However, its role in the development of colorectal cancer is unknown. To investigate the significance of HIF-1alpha during colorectal carcinogenesis and progression we examined its expression in precursor lesions constituting the conventional and serrated pathways, as well as in non-metastatic and metastatic adenocarcinomas.

Hypoxia-induced epithelial VEGF-C/VEGFR-3 upregulation in carcinoma cell lines.

Adaptation to hypoxia, a universal hallmark of carcinomas, is a critical step for tumor cell survival and growth. One of the principal regulators of hypoxia-responsive pathways is the transcription factor hypoxia-inducible factor-1 alpha (HIF-1 alpha). Currently, it is known that tumoral production of members of the vascular endothelial growth factor (VEGF)-family (VEGFs) may promote tumor growth and progression by acting on carcinoma cells that express the cognate receptors (VEGFRs).

Progression of colorectal cancers correlates with overexpression and loss of polarization of expression of the htid-1 tumor suppressor.

Recently, we identified htid-1, the human counterpart of the Drosophila tumor suppressor gene lethal(2)tumorous imaginal discs [l(2)tid], as a direct molecular ligand of the adenomatous polyposis coli (APC) tumor suppressor. The gene encodes three cytosolic (Tid50, Tid48 and Tid46) and three mitochondrial (Tid43, Tid40 and Tid38) proteins. In the colorectal epithelium the cytosolic forms hTid50/hTid48 interact under physiological conditions with the N-terminal region of APC.

Epithelial expression of VEGF receptors in colorectal carcinomas and their relationship to metastatic status.

Background: Vascular endothelial growth factor (VEGF), originally identified as an endothelium-specific factor, can also bind to malignant cells, a mechanism by which a tumor could regulate its own progression. The biological effects of VEGF are mediated by three receptors (VEGFRs), VEGFR-1, VEGFR-2 and VEGFR-3. This study aimed at defining the expression of VEGFs in colorectal cancer (CRC) epithelia and their relationship to the metastatic status.

Loss of E-cadherin in the vicinity of necrosis in colorectal carcinomas: association with NFkappaB expression.

The transcription factor NFkappaB regulates the expression of several tumor-related molecules associated with tumor progression and metastasis. However, the precise mechanisms by which its activation mediates these processes in diverse tumors are unknown. In this study we determined the expression of NFkappaB in various colorectal carcinoma cell lines, in a series of 90 non-metastatic and metastatic colorectal tumors and in an in vitro 3D-spheroid model of HT-29 cells simulating morphological hallmark of these adenocarcinomas, namely neoplastic glandular nests around a necrotic center.

Reduced expression of TLR4 is associated with the metastatic status of human colorectal cancer.

Signaling mediating colorectal cancer (CRC) progression is incompletely understood. Previously, we identified lipopolysaccharide (LPS), an endotoxin of ubiquitously existing colonic bacteria, as a pivotal stimulus increasing the metastatic potential of human CRC. Since the ubiquitous colonic bacteria release large amounts of LPS this observation could be of enormous relevance for the progression of CRC.

Chemokine receptor CCR7 enhances intrahepatic and lymphatic dissemination of human hepatocellular cancer.

Despite many pathophysiological analyses, the process of tumor dissemination of hepatocellular carcinoma (HCC) remains vague. In diverse tumor entities, expression of the chemokine receptor, CCR7, has been linked to tumor dissemination and poor prognosis. Therefore, we evaluated, whether CCR7 exerts similar effects in human HCC.

Local staging of rectal carcinoma and assessment of the circumferential resection margin with high-resolution MRI using an integrated parallel acquisition technique.

Purpose: To assess the diagnostic accuracy of integrated parallel acquisition technique (iPAT) in local staging of rectal carcinoma in comparison to conventional high-resolution MRI.

Materials And Methods: A total of 28 patients with a neoplasm of the rectum and 15 control patients underwent MRI of the pelvis. High-resolution images were acquired conventionally and with iPAT using a modified sensitivity encoding (mSENSE).

Effect of chemokine receptors CXCR4 and CCR7 on the metastatic behavior of human colorectal cancer.

Purpose: The expression of chemokine receptors CXCR4 and CCR7 has been associated with tumor dissemination and poor prognosis in a limited number of tumor entities. However, no data are currently available on the impact of chemokine receptor expression on disease progression and prognosis in human colorectal cancer.

Experimental Design: The expression of CXCR4 and CCR7 was evaluated in 96 patients with histologically confirmed colorectal cancers and in four colorectal cancer cell lines by immunohistochemical staining.

Differential endothelial CAM-expression after stimulation with supernatants of LPS- and cytokine-stimulated HT-29 and ST-ML-12 tumor cells growing as monolayer cultures and multicellular spheroids.

The mechanisms of tumor metastasis in vitro have been principally investigated using monolayer culture systems. In vivo, however, multicellular clusters of tumor cells rather than individual cells appear to penetrate the microvasculature. Thus, the multicellular tumor spheroid model represents a more suitable tool to study tumor cell-endothelial interactions.