Michael O. Idowu

Identification of a Novel Cell Death Receptor Mediating IGFBP-3-induced Anti-tumor Effects in Breast and Prostate Cancer

Insulin-like growth factor-binding protein-3 (IGFBP-3), a major regulator of endocrine actions of IGFs, is a p53-regulated potent apoptotic factor and is significantly suppressed in a variety of cancers. Recent epidemiologic studies suggest that IGFBP-3 contributes to cancer risk protection in a variety of cancers, and a polymorphic variation of IGFBP-3 influences cancer risk, although other studies vary in their conclusions. Some antiproliferative actions of IGFBP-3 have been reported to be independent of IGFs, but the precise biochemical/molecular mechanisms of IGF-independent, antiproliferative actions of IGFBP-3 are largely unknown. Here we report a new cell death receptor, IGFBP-3R, that is a single-span membrane protein and binds specifically to IGFBP-3 but not other IGFBP species. Expression analysis of IGFBP-3 and IGFBP-3R indicates that the IGFBP-3/IGFBP-3R axis is impaired in breast and prostate cancer. We also provide evidence for anti-tumor effect of IGFBP-3R in vivo using prostate and breast cancer xenografts in athymic nude mice. Further in vitro studies demonstrate that IGFBP-3R mediates IGFBP-3-induced caspase-8-dependent apoptosis in various cancer cells. Knockdown of IGFBP-3R attenuated IGFBP-3-induced caspase activities and apoptosis, whereas overexpression of IGFBP-3R enhanced IGFBP-3 biological effects. IGFBP-3R physically interacts and activates caspase-8, and knockdown of caspase-8 expression or activity inhibited IGFBP-3/IGFBP-3R-induced apoptosis. Here, we propose that IGFBP-3R represents a novel cell death receptor and is essential for the IGFBP-3-induced apoptosis and tumor suppression. Thus, the IGFBP-3/IGFBP-3R axis may provide therapeutic and prognostic value for the treatment of cancer.

Severity of Nonalcoholic Fatty Liver Disease and Progression to Cirrhosis Are Associated With Atherogenic Lipoprotein Profile

BACKGROUND & AIMS Nonalcoholic fatty liver disease (NAFLD) is associated independently with increased cardiovascular mortality. Although NAFLD is associated with dyslipidemia, it is not clear whether recently identified markers of cardiovascular risk indicate liver disease progression in patients with histologically confirmed NAFLD. We evaluated an extensive panel of serum markers of cardiovascular risk in nondiabetic patients with histologically proven NAFLD. METHODS We performed a case-control study in which we compared serum levels of laboratory markers of cardiovascular risk among 81 nondiabetic subjects with histologically confirmed NAFLD vs lean (N = 81) and obese (N = 81) individuals without NAFLD (based on liver fat score, controls). For ex vivo studies, liver tissues were obtained from subjects undergoing elective cholecystectomy or from a tissue repository. RESULTS Subjects with NAFLD had increased serum levels of insulin, triglycerides, and apolipoprotein B; increased size and concentration of very large density lipoprotein particles; increased concentrations of low-density lipoprotein (LDL) particles and small dense LDL (sdLDL) cholesterol, and an increased percentage of sdLDL, compared with controls. Although nonalcoholic steatohepatitis was associated with a worse profile of serum atherogenic markers than NAFLD, these differences did not reach statistical significance. Despite hyperinsulinemia, triglyceride and apolipoprotein B levels, concentrations of LDL particles and LDL cholesterol, and sdLDL-related parameters decreased significantly in patients with cirrhosis. Ex vivo studies showed that patients with NAFLD had increased sensitivity of hepatic triglyceride levels and cholesterol synthesis to insulin, and that sensitivity increased the development of cirrhosis. CONCLUSIONS Atherogenic dyslipidemia is related to increased insulin-induced hepatic lipid synthesis in patients with NAFLD. Reduced dyslipidemia in patients with cirrhosis is associated with increased insulin resistance and possibly failed lipid synthesis.

Mesenchymal stem cells in mammary adipose tissue stimulate progression of breast cancer resembling the basal-type

Data are accumulating to support a role for adipose-derived mesenchymal stem cells (MSCs) in breast cancer progression; however, to date most studies have relied on adipose MSCs from non-breast sources. There is a particular need to investigate the role of adipose MSCs in the pathogenesis of basal-like breast cancer, which develops at a disproportionate rate in pre-menopausal African-American women with a gain in adiposity. The aim of this study was to better understand how breast adipose MSCs (bMSCs) contribute to the progression of basal-like breast cancers by relying on isogenic HMT-3255 S3 (pre-invasive) and T4-2 (invasive) human cells that upon transplantation into nude mice resemble this tumor subtype. In vitro results suggested that bMSCs may contribute to breast cancer progression in multiple ways. bMSCs readily penetrate extracellular matrix components in part through their expression of matrix metalloproteinases 1 and 3, promote the invasion of T4-2 cells and efficiently chemoattract endothelial cells via a bFGF-independent, VEGF-A-dependent manner. As mixed xenografts, bMSCs stimulated the growth, invasion and desmoplasia of T4-2 tumors, yet these resident stem cells showed no observable effect on the progression of pre-invasive S3 cells. While bMSCs form vessel-like structures within Matrigel both in vitro and in vivo and chemoattract endothelial cells, there appeared to be no difference between T4-2/bMSC mixed xenografts and T4-2 xenografts with regard to intra- or peri-tumoral vascularity. Collectively, our data suggest that bMSCs may contribute to the progression of basal-like breast cancers by stimulating growth and invasion but not vasculogenesis or angiogenesis.

Adequacy of surgical pathology reporting of cancer: a College of American Pathologists Q-Probes study of 86 institutions.

CONTEXT Inclusion of all scientifically validated elements in surgical pathology cancer reports is needed for optimal patient care. OBJECTIVE To evaluate the frequency with which surgical pathology cancer reports contain all the scientifically validated elements required by the American College of Surgery (ACS) Commission on Cancer (CoC), the extent to which checklists are used, and the effects that the use of checklists have on the completeness of cancer reports. DESIGN Participants in the College of American Pathologists voluntary Q-Probes program reviewed 25 consecutive surgical pathology reports to include cancer reports from breast, colon, rectum, and prostate cancer specimens. For each report, the type and total number of missing required elements, deemed essential by the ACS CoC, was recorded. RESULTS A total of 2125 cancer reports were reviewed in 86 institutions; 68.8% of all surgical pathology cancer reports included all the required elements. Institutions in which checklists were routinely used reported all required elements at a higher rate than those that did not use checklists (88% versus 34%), and institutions that had a system in place to track errors also reported all required elements at a higher rate when compared to those that did not have such a system in place (88% versus 68%). The missing mandated elements, common to cancer reports of all tumor types, were extent of invasion and status of the resection margin. CONCLUSIONS This study demonstrates that about 30% of cancer reports do not have all the scientifically validated elements required by the ACS CoC. Pathology departments in which checklists are not routinely used have a substantially lower rate of reports that include all the required elements.

Mislabeling of Cases, Specimens, Blocks, and Slides A College of American Pathologists Study of 136 Institutions

CONTEXT Accurate specimen labeling is a major patient-safety initiative by the Joint Commission and the College of American Pathologists. Inadequate specimen labels have led to patient injury from wrong patient diagnosis, wrong side treatment, and delay in diagnosis. OBJECTIVES To quantify the rates of mislabeled cases, specimens, blocks, and slides and to identify the sources of error and the ways in which errors are detected. DESIGN In this voluntary-subscription Q-Probes study, participants prospectively reviewed surgical pathology cases for 8 weeks or until 30 errors (mislabeled cases, specimens, blocks, and slides) were identified. Information collected on each labeling error included the work location where the defect occurred, what was mislabeled, the number of items affected, the point of detection, and the consequences of the mislabeling error, along with institutional demographics and practice. The rates of mislabeled cases, specimens, blocks, and slides were tested for association with institutional demographics and practice variables. RESULTS Of the 136 institutions providing information on a total of 1811 mislabeling occurrences, the overall mislabeling rates per 1000 were 1.1 cases, 1.0 specimen, 1.7 blocks, and 1.1 slides. Of all mislabeling events, 27.1% were cases, 19.8% specimens, 25.5% blocks, and 27.7% slides. The work locations at which the errors occurred were 20.9% before accessioning, 12.4% at accessioning, 21.7% at block labeling, 10.2% during gross pathology, and 30.4% at tissue cutting. Errors were typically detected in the first or second steps immediately following the error. Lower mislabeled slide rates were associated with continuous individual case accessioning and use of formal checks at accessioning. Routinely including a statement in the gross description that the specimen is labeled with the patients name and is properly identified was also associated with lower rates of specimen mislabeling. The errors were corrected before reports were issued 96.7% of the time; for 3.2% of errors, a corrected report was issued. In 1.3% of error occurrences, participants gauged that patient care was affected. CONCLUSIONS This study quantified mislabeling rates across 136 institutions of cases (0.11%), specimens (0.1%), blocks (0.17%), and slides (0.11%). Errors in labeling appear nearly equally throughout the system of accessioning, gross pathology processing, and tissue cutting. Errors are typically detected in the immediate steps after the errors occurred, reinforcing the need for quality checks throughout the system.

Attenuation of Sepsis-induced Organ Injury in Mice by Vitamin C

BACKGROUND Multiple organ dysfunction syndrome (MODS) is the principal cause of death in patients with sepsis. Recent work supports the notion that parenteral vitamin C (VitC) is protective in sepsis through pleiotropic mechanisms. Whether suboptimal levels of circulating VitC increase susceptibility to sepsis-induced MODS is unknown. MATERIALS AND METHODS Unlike mice, humans lack the ability to synthesize VitC because of loss of L-gulono-γ-lactone oxidase (Gulo), the final enzyme in the biosynthesis of VitC. To examine whether physiological levels of VitC are required for defense against a catastrophic infection, we induced sepsis in VitC sufficient and VitC deficient Gulo(-/-) mice by intraperitoneal infusion of a fecal stem solution (FIP). Some VitC deficient Gulo(-/-) mice received a parenteral infusion of ascorbic acid (AscA, 200 mg/kg) 30 minutes after induction of FIP. We used molecular, histological, and biochemical analyses to assess for MODS as well as abnormalities in the coagulation system and circulating blood cells. RESULTS FIP produced injury to lungs, kidneys and liver (MODS) in VitC deficient Gulo(-/-) mice. MODS was not evident in FIP-exposed VitC sufficient Gulo(-/-) mice and attenuated in VitC deficient Gulo(-/-) mice infused with AscA. Septic VitC deficient Gulo(-/-) mice developed significant abnormalities in the coagulation system and circulating blood cells. These were attenuated by VitC sufficiency/infusion in septic Gulo(-/-) mice. CONCLUSIONS VitC deficient Gulo(-/-) mice were more susceptible to sepsis-induced MODS. VitC sufficiency or parenteral infusion of VitC, following induction of sepsis, normalized physiological functions that attenuated the development of MODS in sepsis.

The presence and severity of nonalcoholic steatohepatitis is associated with specific changes in circulating bile acids

The histologic spectrum of nonalcoholic fatty liver disease (NAFLD) includes fatty liver (NAFL) and steatohepatitis (NASH), which can progress to cirrhosis in up to 20% of NASH patients. Bile acids (BA) are linked to the pathogenesis and therapy of NASH. We (1) characterized the plasma BA profile in biopsy‐proven NAFL and NASH and compared to controls and (2) related the plasma BA profile to liver histologic features, disease activity, and fibrosis. Liquid chromatography/mass spectrometry quantified BAs. Descriptive statistics, paired and multiple group comparisons, and regression analyses were performed. Of 86 patients (24 controls, 25 NAFL, and 37 NASH; mean age 51.8 years and body mass index 31.9 kg/m2), 66% were women. Increased total primary BAs and decreased secondary BAs (both P < 0.05) characterized NASH. Total conjugated primary BAs were significantly higher in NASH versus NAFL (P = 0.047) and versus controls (P < 0.0001). NASH had higher conjugated to unconjugated chenodeoxycholate (P = 0.04), cholate (P = 0.0004), and total primary BAs (P < 0.0001). The total cholate to chenodeoxycholate ratio was significantly higher in NAFLD without (P = 0.005) and with (P = 0.02) diabetes. Increased key BAs were associated with higher grades of steatosis (taurocholate), lobular (glycocholate) and portal inflammation (taurolithocholate), and hepatocyte ballooning (taurocholate). Conjugated cholate and taurocholate directly and secondary to primary BA ratio inversely correlated to NAFLD activity score. A higher ratio of total secondary to primary BA decreased (odds ratio, 0.57; P = 0.004) and higher conjugated cholate increased the likelihood of significant fibrosis (F≥2) (P = 0.007). Conclusion: NAFLD is associated with significantly altered circulating BA composition, likely unaffected by type 2 diabetes, and correlated with histological features of NASH; these observations provide the foundation for future hypothesis‐driven studies of specific effects of BAs on specific aspects of NASH. (Hepatology 2018;67:534‐548).

Merkel cell carcinoma: a report of gastrointestinal metastasis and review of the literature.

Merkel cell carcinoma (MCC) is an uncommon, highly aggressive cutaneous neoplasm of neuroendocrine differentiation with a poor prognosis. MCC most often presents as a painless, firm, raised lesion in sun-exposed sites of the head and neck region of the elderly. We report a case of a metastatic MCC to the stomach presenting as upper gastrointestinal bleeding. To our knowledge, this is the second reported case of MCC presenting as upper gastrointestinal bleeding and the first case confirmed by the newer immunohistochemical techniques. The literature is reviewed.

Tumor escape and progression of HER-2/neu negative breast cancer under immune pressure

BackgroundEmerging data from pre-clinical and clinical studies suggest that HER-2/neu-specific T cell responses could induce HER-2/neu antigen loss in the tumor cells. These data suggest that patients with HER-2/neu negative breast cancer might have had HER-2/neu positive premalignant lesions in the past that progressed to HER-2/neu negative breast cancer under HER-2/neu-specific immune pressure.MethodsWe conducted a pilot study in patients with HER-2/neu positive and HER-2/neu negative breast cancers as well as a patient with ductal carcinoma in situ (DCIS). HER-2/neu expression was determined by FISH. HER-2/neu-specific T cell responses were determined by using IFN-γ ELISA. Expression of IFN-γ Rα in the tumors was determined by immunohistochemistry analysis of paraffin-embedded tissues.ResultsWe determined that majority of (10 of 12) patients with HER-2/neu negative breast cancer had HER-2/neu-specific IFN-γ producing T cell responses which was stronger than those in patients with HER-2/neu positive tumors. Such immune responses were associated with nuclear translocation of IFN-γ Rα in their tumor cells. Patient with DCIS also showed HER-2/neu-specific T cell responses.ConclusionThese data suggest that conducting retrospective studies in patients with HER-2/neu negative breast cancers and prospective studies in patients with HER-2/neu positive DCIS can determine whether HER-2/neu negative invasive carcinomas arise from HER-2/neu positive DCIS under the immune pressure.

Elevated expression of nuclear Hsp90 in invasive breast tumors

With the current trend for early breast cancer detection, there is also a growing demand for discovering markers to assist in the patient risk stratification. Molecular chaperones play essential roles in the post-translational maturation of oncogenic client proteins and are strongly associated with carcinogenesis. To better define the role of chaperones in breast cancer, tissue arrays were immunostained for the chaperones Hsp90 and p23 and assessed in terms of reactivity, intensity, and cellular localization. Cytoplasmic Hsp90 protein expression was significantly stronger in ductal carcinoma in situ and invasive breast carcinomas as compared to normal breast tissue (p