Robert J. Coffey

Up-regulation of cyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas

BACKGROUND/AIMS Several clinical, epidemiological, and animal studies indicate that nonsteroidal anti-inflammatory drugs (NSAIDs) may alter the incidence of colorectal cancer. A likely target for NSAIDs is cyclooxygenase, a key enzyme in arachidonic acid metabolism. Two isoforms of this enzyme have been identified; cyclooxygenase (COX) 1 and COX-2. The present study was undertaken to determine if there is differential expression of these isoforms in colorectal neoplasia, and, if so, at what stage in malignant transformation this occurs. METHODS COX-1 and COX-2 messenger RNA (mRNA) levels were determined by Northern blot analysis of poly(A)+ RNA isolated from human colorectal cancers, adenomas, and accompanying normal mucosa. RESULTS There was a marked increase in COX-2 mRNA levels in 12 of 14 carcinomas (86%) compared with paired normal mucosa. In contrast, there was equivalent intensity of the COX-1 mRNA transcript between the normal mucosa and cancer in all 14 cases. In six pairs of colorectal adenomas and normal mucosa, three showed up-regulation of COX-2 in the adenoma compared with the normal mucosa. Because COX-2 expression is low to undetectable in normal colorectal mucosa, 14 unpaired adenomas were examined for COX-2 expression; a clearly detectable transcript was identified in six (43%). CONCLUSIONS COX-2, but not COX-1, gene expression is markedly elevated in most human colorectal cancers compared with accompanying normal mucosa. Furthermore, COX-2 expression seems to be increased in a subset of adenomas. COX-2 may provide an attractive therapeutic target in colorectal neoplasia.

Electrical stimulation of the anterior nucleus of thalamus for treatment of refractory epilepsy.

Purpose:  We report a multicenter, double‐blind, randomized trial of bilateral stimulation of the anterior nuclei of the thalamus for localization‐related epilepsy.

Randomized controlled trial of intraputamenal glial cell line-derived neurotrophic factor infusion in Parkinson disease.

Glial cell line–derived neurotrophic factor (GDNF) exerts potent trophic influence on midbrain dopaminergic neurons. This randomized controlled clinical trial was designed to confirm initial clinical benefits observed in a small, open‐label trial using intraputamenal (Ipu) infusion of recombinant human GDNF (liatermin).

Inhibition of human colon cancer cell growth by selective inhibition of cyclooxygenase-2.

A considerable amount of evidence collected from several different experimental systems indicates that cyclooxygenase-2 (COX-2) may play a role in colorectal tumorigenesis. Large epidemiologic studies have shown a 40-50% reduction in mortality from colorectal cancer in persons taking aspirin or other nonsteroidal antiinflammatory drugs on a regular basis. One property shared by all of these drugs is their ability to inhibit COX, a key enzyme in the conversion of arachidonic acid to prostaglandins. Two isoforms of COX have been characterized, COX-1 and COX-2. COX-2 is expressed at high levels in intestinal tumors in humans and rodents. In this study, we selected two transformed human colon cancer cell lines for studies on the role of COX-2 in intestinal tumorigenesis. We evaluated HCA-7 cells which express high levels of COX-2 protein constitutively and HCT-116 cells which lack COX-2 protein. Treatment of nude mice implanted with HCA-7 cells with a selective COX-2 inhibitor (SC-58125), reduced tumor formation by 85-90%. SC-58125 also inhibited colony formation of cultured HCA-7 cells. Conversely, SC-58125 had no effect on HCT-116 implants in nude mice or colony formation in culture. Here we provide evidence that there may be a direct link between inhibition of intestinal cancer growth and selective inhibition of the COX-2 pathway.

A multi-institutional experience with stereotactic radiosurgery for solitary brain metastasis

PURPOSE A multi-institutional experience in radiosurgery for solitary brain metastases was combined to identify factors associated with safety, efficacy, tumor control, and survival. MATERIALS AND METHODS A review of 116 patients with solitary brain metastases who underwent gamma knife stereotactic radiosurgery at five institutions was performed. The median follow-up was 7 months following radiosurgery and 12 months following diagnosis. Minimum tumor doses varied from 8-30 Gy (mean, 17.5 Gy). Forty-five patients failed prior radiotherapy and 71 had no prior brain irradiation. Fifty-one patients had radiosurgery alone and 65 underwent combined radiosurgery with fractionated large-field radiotherapy (mean dose, 33.8 Gy). RESULTS Median survival was 11 months after radiosurgery and 20 months after diagnosis. Follow-up documented local tumor control in 99 patients (85%), tumor recurrence in 17 (15%), and documented radiation necrosis in one (1%). The 2-year actuarial tumor control rate was 67 +/- 8%. Tumor histology affected survival (better for breast cancer, p = .004) and local control (better for melanoma and renal cell, p = .0003) in multivariate analyses. Combined fractionated radiotherapy and radiosurgery improved local control (p = 0.111), but not survival in multivariate testing. CONCLUSION Radiosurgery is effective in controlling solitary brain metastases with low morbidity. Further study is needed to better define optimum treatment parameters for radiosurgery.

EGF receptor ligands

Publisher Summary This chapter focuses on epidermal growth factor (EGF) receptor ligands. The mammalian ligands that bind the EGF receptor (EGFR [HER1, Erb-B1]) include EGF, transforming growth factor-α (TGFα), heparin-binding EGF-like growth factor (HB-EGF), amphiregulin (AR), betacellulin (BTC), epiregulin (EPR), and epigen [1–4,24]. Each of the mature peptide growth factors is characterized by a consensus sequence consisting of six spatially conserved cysteine residues (CX7 CX4–5 CX10–13 CXCX8 C) that form three intramolecular disulfide bonds. In addition to binding EGFR, HB-EGF, BTC, and EPR are reported to also bind HER4. Mature HB-EGF and AR also contain an amino-terminal heparin-binding domain (HBD). All ligands are made as type I transmembrane proteins that are inserted into the plasma membrane and then cleaved by cell surface proteases to release mature growth factor that binds EGFR. The rapid local capture of TGFα by the EGFR has fundamental biological importance and is a phenomenon that is critical in diverse biological processes such as vulva development in the nematode Caenorhabditis elegans (C. elegans) and hair follicle organization in mammals. Rapid consumption of TGFα by EGFR also appears to be important in mammalian hair follicle development. If this signaling is disrupted, as in the case of TGFα and EGFR null mice, the hair follicle is disorganized, resulting in an overt phenotype of wavy whiskers and lack of proper coat development.

Synergistic interaction between hypergastrinemia and Helicobacter infection in a mouse model of gastric cancer.

BACKGROUND & AIMS Hypergastrinemia occurs frequently in association with acid suppression and Helicobacter infection, but its role in the progression to gastric atrophy and gastric cancer has not been well defined. METHODS The effects of hypergastrinemia, and possible synergy with Helicobacter felis infection, were investigated in insulin-gastrin (INS-GAS) transgenic mice. RESULTS INS-GAS mice initially showed mild hypergastrinemia, increased maximal gastric acid secretion, and increased parietal cell number but later progressed to decreased parietal cell number and hypochlorhydria. Development of gastric atrophy was associated with increased expression of growth factors, heparin-binding epidermal growth factor and transforming growth factor alpha. At 20 months of age, INS-GAS mice showed no evidence of increased enterochromaffin-like cell number, but instead exhibited gastric metaplasia, dysplasia, carcinoma in situ, and gastric cancer with vascular invasion. Invasive gastric carcinoma was observed in 6 of 8 INS-GAS mice that were >20 months old. Helicobacter felis infection of INS-GAS mice led to accelerated (< or = 8 mo) development of intramucosal carcinoma (85%), with submucosal invasion (54%) and intravascular invasion (46%; P < or = 0.05). CONCLUSIONS These findings support the unexpected conclusion that chronic hypergastrinemia in mice can synergize with Helicobacter infection and contribute to eventual parietal cell loss and progression to gastric cancer.

Proteogenomic characterization of human colon and rectal cancer

Extensive genomic characterization of human cancers presents the problem of inference from genomic abnormalities to cancer phenotypes. To address this problem, we analysed proteomes of colon and rectal tumours characterized previously by The Cancer Genome Atlas (TCGA) and perform integrated proteogenomic analyses. Somatic variants displayed reduced protein abundance compared to germline variants. Messenger RNA transcript abundance did not reliably predict protein abundance differences between tumours. Proteomics identified five proteomic subtypes in the TCGA cohort, two of which overlapped with the TCGA ‘microsatellite instability/CpG island methylation phenotype’ transcriptomic subtype, but had distinct mutation, methylation and protein expression patterns associated with different clinical outcomes. Although copy number alterations showed strong cis- and trans-effects on mRNA abundance, relatively few of these extend to the protein level. Thus, proteomics data enabled prioritization of candidate driver genes. The chromosome 20q amplicon was associated with the largest global changes at both mRNA and protein levels; proteomics data highlighted potential 20q candidates, including HNF4A (hepatocyte nuclear factor 4, alpha), TOMM34 (translocase of outer mitochondrial membrane 34) and SRC (SRC proto-oncogene, non-receptor tyrosine kinase). Integrated proteogenomic analysis provides functional context to interpret genomic abnormalities and affords a new paradigm for understanding cancer biology.

Development of mammary hyperplasia and neoplasia in MMTV-TGFα transgenic mice

Abstract To study the role of transforming growth factor α (TGFα) in normal mammary development and mammary neoplasia in vivo, we have generated transgenic mice in which a human TGFα cDNA is expressed under the control of the MMTV enhancer/promoter. Overexpression of TGFα in the mammary epithelium, as confirmed by in situ hybridization and immunohistochemistry, is associated with hyperplasia of alveoli and terminal ducts in virgin female and pregnant transgenic mice. A range of morphologic abnormalities including lobular hyperplasia, cystic hyperplasia, adenoma, and adenocarcinoma is seen in mammary tissue of transgenic females. In contrast, no morphologic abnormalities are seen in transgenic males in spite of TGFα overexpression in salivary glands and reproductive organs. TGFα can therefore act as an oncogene in vivo and appears to predispose mammary epithelium to neoplasia and carcinoma.

Cholangiocarcinoma complicating primary sclerosing cholangitis

Clinical experience and pathologic evidence strongly support an association between PSC and cholangiocarcinoma. Cholangiocarcinoma arises in 5 to 10% of patients with preexisting PSC and can also present in a synchronous fashion with PSC. Cholangiocarcinoma complicating PSC is heralded by rapid clinical deterioration with progressive jaundice, weight loss, and abdominal discomfort. These tumors have been most frequently detected at an advanced stage, which precludes potentially curative resection. Liver transplantation for locally advanced and incidentally discovered tumors has been fraught with frequent tumor recurrence. Regardless of therapy, the prognosis for patients with cholangiocarcinoma complicating PSC has been uniformly poor. There is a clear need for heightened clinical awareness, methods for earlier detection, and effective therapy for patients with cholangiocarcinoma complicating PSC.