CD163 expression in leukemia cutis

Background: Proper diagnosis of myeloid leukemia cutis (LC) is of great clinical importance but can be difficult because no single immunohistochemical marker is adequately sensitive or specific for definitive diagnosis. Thus, a broader panel of markers is often desirable. CD163 is highly specific for normal and neoplastic cells of the monocyte/histiocyte lineage. In this study, we examined the value of CD163 in the diagnosis of acute myeloid LC. Methods: A total of 34 cases, including 18 cases of myelomonocytic or monocytic LC, 10 cases of myeloid LC without monocytic component and 6 cases of acute lymphoblastic leukemia/lymphoma (ALL), were stained with CD163. Results: CD163 was expressed in 8 of 18 (44%) of myelomonocytic or monocytic LC and 1 of 10 (10%) of other myeloid LC, but in none of the ALL cases (0/6). CD163 was highly specific (90%) for myeloid LC with a monocytic component, but showed low sensitivity in the diagnosis of both myeloid LC in general (24%) and myeloid LC with a monocytic component (44%). Conclusions: Our results suggest that CD163 has utility as a specific marker for myeloid LC in conjunction with currently used immunohistochemical stains, but should not be used alone for diagnosis.Harms PW, Bandarchi B, Ma L. CD163 expression in leukemia cutis.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/78608/1/j.1600-0560.2010.01533.x.pd

From Melanocyte to Metastatic Malignant Melanoma

Malignant melanoma is one of the most aggressive malignancies in human and is responsible for almost 60% of lethal skin tumors. Its incidence has been increasing in white population in the past two decades. There is a complex interaction of environmental (exogenous) and endogenous, including genetic, risk factors in developing malignant melanoma. 8–12% of familial melanomas occur in a familial setting related to mutation of the CDKN2A gene that encodes p16. The aim of this is to briefly review the microanatomy and physiology of the melanocytes, epidemiology, risk factors, clinical presentation, historical classification and histopathology and, more in details, the most recent discoveries in biology and genetics of malignant melanoma. At the end, the final version of 2009 AJCC malignant melanoma staging and classification is presented

Lipocalin2 Promotes Invasion, Tumorigenicity and Gemcitabine Resistance in Pancreatic Ductal Adenocarcinoma

<div><p>Lipocalin 2 (LCN2) is a small secreted protein and its elevated expression has been observed in pancreatic as well as other cancer types. LCN2 has been reported to promote resistance to drug-induced apoptosis, enhance invasion through its physical association with matrix metalloproteinase-9, and promote <em>in vivo</em> tumor growth. LCN2 was found to be commonly expressed in patient PDAC samples and its pattern of immunohistochemical staining intensified with increasing severity in high-grade precursor lesions. Downregulation of LCN2 in two pancreatic ductal adenocarcinoma cell lines (BxPC3 and HPAF-II) with high LCN2 expression significantly reduced attachment, invasion, and tumour growth <em>in vivo</em>, but not proliferation or motility. Downregulation of LCN2 in two pancreatic ductal adenocarcinoma cell lines (BxPC3 and HPAF-II) with high expression significantly reduced attachment, invasion, and tumour growth <em>in vivo</em>. In contrast, LCN2 overexpression in PANC1, with low endogenous expression, significantly increased invasion, attachment, and enhanced tumor growth. Suppression of LCN2 in BxPC3 and HPAF-II cells increased their sensitivity to gemcitabine <em>in vitro</em>, and <em>in vivo</em> when BxPC3 was tested. Furthermore, LCN2 promotes expression of VEGF and HIF1A which contribute to enhanced vascularity. These overall results demonstrate that LCN2 plays an important role in the malignant progression of pancreatic ductal carcinoma and is a potential therapeutic target for this disease.</p> </div

Glycogen Synthase Kinase-3 Inhibition Sensitizes Pancreatic Cancer Cells to TRAIL-Induced Apoptosis

<div><p>Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) induces apoptosis in a variety of cancer cell lines with little or no effect on normal cells. However, its effect is limited as some cancers including pancreatic cancer show de novo resistance to TRAIL induced apoptosis. In this study we report that GSK-3 inhibition using the pharmacologic agent AR-18, enhanced TRAIL sensitivity in a range of pancreatic and prostate cancer cell lines. This sensitization was found to be caspase-dependent, and both pharmacological and genetic knock-down of GSK-3 isoforms resulted in apoptotic features as shown by cleavage of PARP and caspase-3. Elevated levels of reactive oxygen intermediates and disturbance of mitochondrial membrane potential point to a mitochondrial amplification loop for TRAIL-induced apoptosis after GSK-3 inhibition. Consistent with this, overexpression of anti-apoptotic mitochondrial targets such as Bcl-XL, Mcl-1, and Bcl-2 rescued PANC-1 and PPC-1 cells from TRAIL sensitization. However, overexpression of the caspase-8 inhibitor CrmA also inhibited the sensitizing effects of GSK-3 inhibitor, suggesting an additional role for GSK-3 that inhibits death receptor signaling. Acute treatment of mice bearing PANC-1 xenografts with a combination of AR-18 and TRAIL also resulted in a significant increase in apoptosis, as measured by caspase-3 cleavage. Sensitization to TRAIL occurred despite an increase in β-catenin due to GSK-3 inhibition, suggesting that the approach might be effective even in cancers with dysregulated β-catenin. These results suggest that GSK-3 inhibitors might be effectively combined with TRAIL for the treatment of pancreatic cancer.</p> </div

TRAIL sensitization by AR18 is associated with loss of ΔΨm and increased ROI generation.

<p>PANC-1 and BxPC-3 cells were untreated or incubated with AR-18 (25 µM), TRAIL (10 ng/mL), or their combination for 24 h, and then analyzed by flow cytometry. Dot density plots of propidium iodide (PI) uptake vs ΔΨm show that loss of ΔΨm precedes PI uptake. TRAIL induced loss of ΔΨm in BxPC-3 but not in PANC-1, consistent with their greater sensitivity seen using the SRB assay (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0041102#pone-0041102-g001" target="_blank">Figure 1</a>). Combined treatment with TRAIL and AR18 clearly sensitized both cell lines to loss of ΔΨm, and this was accompanied by increased ROI generation and loss of out membrane integrity.</p

LCN2 promotes survival and adhesion.

<p>(A) LCN2 enhances the expression of anti-apoptotic genes and downregulated the pro-apoptotic genes. (B) LCN2 enhances adhesion and ECM. Target genes whose expression was up/downregulated by at least 1.5-fold in the control cell line and xenograft samples compared to the LCN2 downregulated cell line and xenograft samples. Red triangles denote increased expression and green triangles denote decreased expression. The mRNA expression of (C) AIFM, (D) BIRC2, (E) FAIM, (F) MCL-1, (G) LAMAC2, (H) MMP7, (I) CDH11, and (J) ITGA2 were assessed in BxPC3, HPAF-II, and PANC1 cell lines. (* denotes significant differences between the test and control samples (p<0.05, student t-tests, n = 3).</p

GSK-3 inhibition enhances TRAIL sensitization through PARP and caspase cleavage.

<p>(A) BxPC-3 and PANC-1 cells were treated with AR-18, in combination with or without TRAIL for 24 h and analysed by for PARP cleavage. (B) BxPC-3 (left) and PANC-1 (right) cells were treated with AR-18 (25 uM), TRAIL (10 ng/mL), z-VAD-fmk 50 µM, or the combinations indicated and SRB assay after 22 h incubation. Each bar graph signifies mean from three experiments with six replicates. error bars  =  ± SEM. *p<0.005, **p<0.0001.</p

GSK-3 inhibition sensitizes TRAIL-resistant pancreatic cancer cells to apoptosis.

<p>PANC-1 (A) and BxPC-3 (B) were treated with TRAIL after 24 h pre-exposure to AR-18 at the indicated concentrations, and cell proliferation measured by SRB assay. Each bar graph signifies mean from three separate experiments with six replicates. error bars  =  ± SEM.</p