CD34

Gene Summary

Gene:CD34; CD34 molecule
Location:1q32
Summary:The protein encoded by this gene may play a role in the attachment of stem cells to the bone marrow extracellular matrix or to stromal cells. This single-pass membrane protein is highly glycosylated and phosphorylated by protein kinase C. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2011]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:hematopoietic progenitor cell antigen CD34
HPRD
Source:NCBIAccessed: 17 August, 2015

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 17 August 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 17 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: CD34 (cancer-related)

Kim JC, Kim KT, Park JT, et al.
Expression of vasohibin-2 in pancreatic ductal adenocarcinoma promotes tumor progression and is associated with a poor clinical outcome.
Hepatogastroenterology. 2015 Mar-Apr; 62(138):251-6 [PubMed] Related Publications
This study aimed to assess the expression of vasohibin-2 (VASH2) in pancreatic ductal adenocarcinoma (PDAC) as a marker of tumor aggressiveness and its impact on tumor angiogenesis, proliferation, and clinical outcome. We examined the expression of the VASH2 gene in human pancreatic cell lines PANC-1 and MiaPaCa-2 by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and immunocytochemistry. Fifty samples from patients with PDAC were immunostained with VASH2, CD34, and Ki-67 antibodies. Further, the immunoreactivity of VASH2 correlated with the pathological features, including microvessel density (MVD), tumor cell proliferation (Ki-67 labeling index), and survival. Forty-seven of the 50 samples from PDAC patients showed immunoreactivity for VASH2 along the tumor cell cytoplasm. Among the VASH2-positive samples, 22 were categorized as high VASH2 expression group, and this group had statistical significance with pN stage (p = 0.006), UICC stage (p = 0.033), tumor proliferation (p < 0.001), and MVD (p = 0.017). Moreover, patients with high VASH2 expression showed worse prognosis compared to those showing low VASH2 expression (overall logrank p = 0.003). Thus, our results suggested that overexpression of VASH2 accelerated the pace of tumor development toward a more serious malignant phenotype and was associated with a poor clinical outcome. VASH2 may be an important novel target for the management of PDAC after surgery.

Verstraete M, Debucquoy A, Dekervel J, et al.
Combining bevacizumab and chemoradiation in rectal cancer. Translational results of the AXEBeam trial.
Br J Cancer. 2015; 112(8):1314-25 [PubMed] Article available free on PMC after 14/04/2016 Related Publications
BACKGROUND: This study characterises molecular effect of bevacizumab, and explores the relation of molecular and genetic markers with response to bevacizumab combined with chemoradiotherapy (CRT).
METHODS: From a subset of 59 patients of 84 rectal cancer patients included in a phase II study combining bevacizumab with CRT, tumour and blood samples were collected before and during treatment, offering the possibility to evaluate changes induced by one dose of bevacizumab. We performed cDNA microarrays, stains for CD31/CD34 combined with α-SMA and CA-IX, as well as enzyme-linked immunosorbent assay (ELISA) for circulating angiogenic proteins. Markers were related with the pathological response of patients.
RESULTS: One dose of bevacizumab changed the expression of 14 genes and led to a significant decrease in microvessel density and in the proportion of pericyte-covered blood vessels, and a small but nonsignificant increase in hypoxia. Alterations in angiogenic processes after bevacizumab delivery were only detected in responding tumours. Lower PDGFA expression and PDGF-BB levels, less pericyte-covered blood vessels and higher CA-IX expression were found after bevacizumab treatment only in patients with pathological complete response.
CONCLUSIONS: We could not support the 'normalization hypothesis' and suggest a role for PDGFA, PDGF-BB, CA-IX and α-SMA. Validation in larger patient groups is needed.

Schinke C, Giricz O, Li W, et al.
IL8-CXCR2 pathway inhibition as a therapeutic strategy against MDS and AML stem cells.
Blood. 2015; 125(20):3144-52 [PubMed] Article available free on PMC after 14/05/2016 Related Publications
Acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are associated with disease-initiating stem cells that are not eliminated by conventional therapies. Novel therapeutic targets against preleukemic stem cells need to be identified for potentially curative strategies. We conducted parallel transcriptional analysis of highly fractionated stem and progenitor populations in MDS, AML, and control samples and found interleukin 8 (IL8) to be consistently overexpressed in patient samples. The receptor for IL8, CXCR2, was also significantly increased in MDS CD34(+) cells from a large clinical cohort and was predictive of increased transfusion dependence. High CXCR2 expression was also an adverse prognostic factor in The Cancer Genome Atlas AML cohort, further pointing to the critical role of the IL8-CXCR2 axis in AML/MDS. Functionally, CXCR2 inhibition by knockdown and pharmacologic approaches led to a significant reduction in proliferation in several leukemic cell lines and primary MDS/AML samples via induction of G0/G1 cell cycle arrest. Importantly, inhibition of CXCR2 selectively inhibited immature hematopoietic stem cells from MDS/AML samples without an effect on healthy controls. CXCR2 knockdown also impaired leukemic growth in vivo. Together, these studies demonstrate that the IL8 receptor CXCR2 is an adverse prognostic factor in MDS/AML and is a potential therapeutic target against immature leukemic stem cell-enriched cell fractions in MDS and AML.

Chandran P, Le Y, Li Y, et al.
Mesenchymal stromal cells from patients with acute myeloid leukemia have altered capacity to expand differentiated hematopoietic progenitors.
Leuk Res. 2015; 39(4):486-93 [PubMed] Related Publications
The bone marrow microenvironment may be permissive to the emergence and progression of acute myeloid leukemia (AML). Studying interactions between the microenvironment and leukemia cells should provide new insight for therapeutic advances. Mesenchymal stromal cells (MSCs) are central to the maintenance of the hematopoietic niche. Here we compared the functions and gene expression patterns of MSCs derived from bone marrow aspirates of healthy donors and patients with AML. MSCs expanded from AML patients had heterogeneous morphology and displayed a wide range of proliferation capacity compared to MSCs from healthy controls. The ability of AML-MSCs to support the expansion of committed hematopoietic progenitors from umbilical cord blood-derived CD34+ cells may be impaired while the expression of genes associated with maintaining hematopoietic quiescence appeared to be increased in AML-MSCs compared to healthy donors. These results highlight important potential differences in the biologic profile of MSCs from AML patients compared to healthy donors that may contribute to the emergence or progression of leukemia.

Ye G, Qin Y, Lu X, et al.
The association of renin-angiotensin system genes with the progression of hepatocellular carcinoma.
Biochem Biophys Res Commun. 2015; 459(1):18-23 [PubMed] Related Publications
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Angiogenesis is reported to play a pivotal role in the occurrence, development and metastasis of HCC. The renin-angiotensin system (RAS) is involved in the regulation of angiogenesis. Here, based on the analysis of HCC datasets from Gene Expression Omnibus (GEO) database and The Cancer Genome Atlas (TCGA), we found that there was a negative correlation between the mRNA levels of angiotensin converting enzyme 2 (ACE2) and CD34. To explore the association of RAS with the progression from fibrosis to cirrhosis to HCC, liver specimens and serum samples were collected from patients with hepatic fibrosis, cirrhosis and HCC. Relative hepatic mRNA levels of CD34 and ACE2 were determined by real-time PCR, and the serum concentrations of Angiotensin II (Ang II), Ang (1-7) and vascular endothelial growth factor (VEGF) were detected by ELISA. We found that ACE2 mRNA was gradually decreased, while CD34 mRNA was progressively increased with the increasing grade of disease severity. Concentrations of Ang II, Ang (1-7) and VEGF were higher in the sera of patients than in that of healthy volunteers. These proteins' concentrations were also progressively increased with the increasing grade of disease severity. Moreover, a positive correlation was found between VEGF and Ang II or Ang (1-7), while negative correlation was observed between mRNA levels of CD34 and ACE2. More importantly, patients with higher level of ACE2 expression had longer survival time than those with lower level of ACE2 expression. Taken together, our data suggests that the low expression of ACE2 may be a useful indicator of poor prognosis in HCC. The RAS may have a role in the progression of HCC.

Nishio J, Iwasaki H, Aoki M, et al.
FDG PET/CT and MR imaging of CD34-negative soft-tissue solitary fibrous tumor with NAB2-STAT6 fusion gene.
Anticancer Res. 2015; 35(2):967-71 [PubMed] Related Publications
Extrapleural solitary fibrous tumor (SFT) is an uncommon mesenchymal neoplasm of intermediate biological potential. Herein, we describe the radiological, histological, immunohistochemical and molecular genetic features of an SFT arising in the left thigh of a 55-year-old woman. Magnetic resonance imaging exhibited a well-defined mass with intermediate signal intensity on T1-weighted sequences and heterogeneous high signal intensity on T2-weighted sequences. Contrast-enhanced T1-weighted sequences showed strong homogeneous enhancement of the mass. A prominent vascular pedicle was visible. Integrated positron-emission tomography (PET)/computed tomographic (CT) scan demonstrated a moderate 18F-fluorodeoxyglucose (FDG) uptake (maximum standardized uptake value, 4.45) in the mass. Following an open biopsy, wide excision of the tumor was performed. Histologically, the tumor was composed of a proliferation of spindle cells in a fibrous stroma with focal hyalinization. Thin-walled branching hemangiopericytoma-like vessels were observed. Immunohistochemically, the tumor cells were diffusely positive for signal transducer and activator of transcription 6 (STAT6) but negative for CD34. The MIB-1 labeling index was less than 5%. Subsequent reverse transcriptase-polymerase chain reaction analysis identified a nerve growth factor inducible-A binding protein 2-STAT6 gene fusion. Our case supports the utility of STAT6 immunohistochemistry as an adjunct in the diagnosis of soft-tissue SFT with loss of CD34 positivity. To the best of our knowledge, this is the first report showing the FDG PET/CT findings of soft-tissue SFT.

Yin P, Ono M, Moravek MB, et al.
Human uterine leiomyoma stem/progenitor cells expressing CD34 and CD49b initiate tumors in vivo.
J Clin Endocrinol Metab. 2015; 100(4):E601-6 [PubMed] Article available free on PMC after 01/04/2016 Related Publications
CONTEXT: Uterine leiomyoma is the most common benign tumor in reproductive-age women. Using a dye-exclusion technique, we previously identified a side population of leiomyoma cells exhibiting stem cell characteristics. However, unless mixed with mature myometrial cells, these leiomyoma side population cells did not survive or grow well in vitro or in vivo.
OBJECTIVE: The objective of this study was to identify cell surface markers to isolate leiomyoma stem/progenitor cells.
DESIGN: Real-time PCR screening was used to identify cell surface markers preferentially expressed in leiomyoma side population cells. In vitro colony-formation assay and in vivo tumor-regeneration assay were used to demonstrate functions of leiomyoma stem/progenitor cells.
RESULTS: We found significantly elevated CD49b and CD34 gene expression in side population cells compared with main population cells. Leiomyoma cells were sorted into three populations based on the expression of CD34 and CD49b: CD34(+)/CD49b(+), CD34(+)/CD49b(-), and CD34(-)/CD49b(-) cells, with the majority of the side population cells residing in the CD34(+)/CD49b(+) fraction. Of these populations, CD34(+)/CD49b(+) cells expressed the lowest levels of estrogen receptor-α, progesterone receptor, and α-smooth muscle actin, but the highest levels of KLF4, NANOG, SOX2, and OCT4, confirming their more undifferentiated status. The stemness of CD34(+)/CD49b(+) cells was also demonstrated by their strongest in vitro colony-formation capacity and in vivo tumor-regeneration ability.
CONCLUSIONS: CD34 and CD49b are cell surface markers that can be used to enrich a subpopulation of leiomyoma cells possessing stem/progenitor cell properties; this technique will accelerate efforts to develop new therapies for uterine leiomyoma.

Akaike K, Kurisaki-Arakawa A, Hara K, et al.
Distinct clinicopathological features of NAB2-STAT6 fusion gene variants in solitary fibrous tumor with emphasis on the acquisition of highly malignant potential.
Hum Pathol. 2015; 46(3):347-56 [PubMed] Related Publications
The impact of NGFI-A binding protein 2 (NAB2)-signal transducer and activator of transcription 6 (STAT6) fusion on the biological behavior and the mechanism of acquisition of malignant phenotype in solitary fibrous tumor (SFT) is not well understood. We examined variations of the NAB2-STAT6 fusion gene in 40 cases of SFT using formalin-fixed, paraffin-embedded tissues and secondary genetic alterations of tumor protein p53 (TP53),, platelet-derived growth factor receptor, β polypeptide (PDGFRB), and telomerase reverse transcriptase (TERT) promoters. These gene variations were compared with the clinicopathological features. The 2-year and 5-year disease-free survival rates (DFSRs) were 91% and 83%, respectively. All 40 samples demonstrated nuclear staining for STAT6, including CD34-negative cases. Moreover, p53-positive staining was associated with a lower DFSR and was significantly associated with higher Ki-67 label index, higher mitotic rate (mitosis, >4/high-power field), and the presence of nuclear atypia/pleomorphism. NAB2-STAT6 fusions were detected in all of the cases; the NAB2 exon 4-STAT6 exon 2, the most common genotype, appeared in 18 cases, which was associated with thoracic tumor location and the less aggressive phenotype. In contrast, tumors with NAB2 exon 6-STAT6 exon 16/18 demonstrated an aggressive phenotype. Mutations in TP53 and PDGFRB were detected in 2 and 3 cases respectively, and these occurred in a mutually exclusive fashion. TERT promoter hot spot mutations were observed in 5 cases, which were associated with shorter DFSR. Two dedifferentiated SFT cases harbored both TP53 and TERT promoter mutations. TP53 mutations, which result in its overexpression, in combination with TERT promoter mutations seem to play an important role in the dedifferentiation process.

Khorashad JS, Eiring AM, Mason CC, et al.
shRNA library screening identifies nucleocytoplasmic transport as a mediator of BCR-ABL1 kinase-independent resistance.
Blood. 2015; 125(11):1772-81 [PubMed] Article available free on PMC after 01/04/2016 Related Publications
The mechanisms underlying tyrosine kinase inhibitor (TKI) resistance in chronic myeloid leukemia (CML) patients lacking explanatory BCR-ABL1 kinase domain mutations are incompletely understood. To identify mechanisms of TKI resistance that are independent of BCR-ABL1 kinase activity, we introduced a lentiviral short hairpin RNA (shRNA) library targeting ∼5000 cell signaling genes into K562(R), a CML cell line with BCR-ABL1 kinase-independent TKI resistance expressing exclusively native BCR-ABL1. A customized algorithm identified genes whose shRNA-mediated knockdown markedly impaired growth of K562(R) cells compared with TKI-sensitive controls. Among the top candidates were 2 components of the nucleocytoplasmic transport complex, RAN and XPO1 (CRM1). shRNA-mediated RAN inhibition or treatment of cells with the XPO1 inhibitor, KPT-330 (Selinexor), increased the imatinib sensitivity of CML cell lines with kinase-independent TKI resistance. Inhibition of either RAN or XPO1 impaired colony formation of CD34(+) cells from newly diagnosed and TKI-resistant CML patients in the presence of imatinib, without effects on CD34(+) cells from normal cord blood or from a patient harboring the BCR-ABL1(T315I) mutant. These data implicate RAN in BCR-ABL1 kinase-independent imatinib resistance and show that shRNA library screens are useful to identify alternative pathways critical to drug resistance in CML.

Hoang VT, Buss EC, Wang W, et al.
The rarity of ALDH(+) cells is the key to separation of normal versus leukemia stem cells by ALDH activity in AML patients.
Int J Cancer. 2015; 137(3):525-36 [PubMed] Related Publications
To understand the precise disease driving mechanisms in acute myeloid leukemia (AML), comparison of patient matched hematopoietic stem cells (HSC) and leukemia stem cells (LSC) is essential. In this analysis, we have examined the value of aldehyde dehydrogenase (ALDH) activity in combination with CD34 expression for the separation of HSC from LSC in 104 patients with de novo AML. The majority of AML patients (80 out of 104) had low percentages of cells with high ALDH activity (ALDH(+) cells; <1.9%; ALDH-rare AML), whereas 24 patients had relatively numerous ALDH(+) cells (≥1.9%; ALDH-numerous AML). In patients with ALDH-rare AML, normal HSC could be separated by their CD34(+) ALDH(+) phenotype, whereas LSC were exclusively detected among CD34(+) ALDH(-) cells. For patients with ALDH-numerous AML, the CD34(+) ALDH(+) subset consisted mainly of LSC and separation from HSC was not feasible. Functional analyses further showed that ALDH(+) cells from ALDH-numerous AML were quiescent, refractory to ARA-C treatment and capable of leukemic engraftment in a xenogenic mouse transplantation model. Clinically, resistance to chemotherapy and poor long-term outcome were also characteristic for patients with ALDH-numerous AML providing an additional risk-stratification tool. The difference in spectrum and relevance of ALDH activity in the putative LSC populations demonstrates, in addition to phenotypic and genetic, also functional heterogeneity of leukemic cells and suggests divergent roles for ALDH activity in normal HSC versus LSC. By acknowledging these differences our study provides a new and useful tool for prospective identification of AML cases in which separation of HSC from LSC is possible.

Aoki Y, Watanabe T, Saito Y, et al.
Identification of CD34+ and CD34- leukemia-initiating cells in MLL-rearranged human acute lymphoblastic leukemia.
Blood. 2015; 125(6):967-80 [PubMed] Article available free on PMC after 01/04/2016 Related Publications
Translocation of the mixed-lineage leukemia (MLL) gene with AF4, AF9, or ENL results in acute leukemia with both lymphoid and myeloid involvement. We characterized leukemia-initiating cells (LICs) in primary infant MLL-rearranged leukemia using a xenotransplantation model. In MLL-AF4 patients, CD34(+)CD38(+)CD19(+) and CD34(-)CD19(+) cells initiated leukemia, and in MLL-AF9 patients, CD34(-)CD19(+) cells were LICs. In MLL-ENL patients, either CD34(+) or CD34(-) cells were LICs, depending on the pattern of CD34 expression. In contrast, in patients with these MLL translocations, CD34(+)CD38(-)CD19(-)CD33(-) cells were enriched for normal hematopoietic stem cells (HSCs) with in vivo long-term multilineage hematopoietic repopulation capacity. Although LICs developed leukemic cells with clonal immunoglobulin heavy-chain (IGH) rearrangement in vivo, CD34(+)CD38(-)CD19(-)CD33(-) cells repopulated recipient bone marrow and spleen with B cells, showing broad polyclonal IGH rearrangement and recipient thymus with CD4(+) single positive (SP), CD8(+) SP, and CD4(+)CD8(+) double-positive (DP) T cells. Global gene expression profiling revealed that CD9, CD32, and CD24 were over-represented in MLL-AF4, MLL-AF9, and MLL-ENL LICs compared with normal HSCs. In patient samples, these molecules were expressed in CD34(+)CD38(+) and CD34(-) LICs but not in CD34(+)CD38(-)CD19(-)CD33(-) HSCs. Identification of LICs and LIC-specific molecules in primary human MLL-rearranged acute lymphoblastic leukemia may lead to improved therapeutic strategies for MLL-rearranged leukemia.

Souza Melo CP, Campos CB, Dutra ÁP, et al.
Correlation between FLT3-ITD status and clinical, cellular and molecular profiles in promyelocytic acute leukemias.
Leuk Res. 2015; 39(2):131-7 [PubMed] Related Publications
Internal tandem duplications (ITD) of FLT3 gene occur in about a third of acute promyelocytic leukemias (APL). We investigated the patterns of blood count, surface antigen, expression, chromosome aberrations, PML-RARa isoform, gene expression profile (GEP) and survival in 34 APL patients according to FLT3-ITD status. 97% had a t(15;17) and all of them carried PML-RARa gene fusion, 8 (23.5%) had a FLT3-ITD mutation. Presence of ITD was associated with higher Hb and WBC levels, bcr3 isoform, CD34 expression, CD2 or CD2/CD34 expression. In a multivariate analysis, Hb>9.6g/dL and WBC≥20 × 10(9)/L were important factors for predicting ITD presence. GEP showed that FLT3-ITD carriers clustered separately, even when as few as 5 genes were considered. This study provides further evidence that FLT3-ITDs carriers constitute a biologically distinct group of APL patients.

Wang LS, Li L, Li L, et al.
MicroRNA-486 regulates normal erythropoiesis and enhances growth and modulates drug response in CML progenitors.
Blood. 2015; 125(8):1302-13 [PubMed] Article available free on PMC after 01/04/2016 Related Publications
MicroRNAs (miRNAs) are key regulators of hematopoietic cell differentiation and may contribute to altered growth of leukemic stem cells. Using microarray-based miRNA profiling, we found that miRNA 486 (miR-486) is significantly upregulated in chronic myeloid leukemia (CML) compared with normal CD34(+) cells, particularly in the megakaryocyte-erythroid progenitor population. miR-486-5p expression increased during erythroid differentiation of both CML and normal CD34(+) cells. Ectopic miR-486-5p expression enhanced in vitro erythroid differentiation of normal CD34(+) cells, whereas miR-486-5p inhibition suppressed normal CD34(+) cell growth in vitro and in vivo and inhibited erythroid differentiation and erythroid cell survival. The effects of miR-486-5p on hematopoietic cell growth and survival are mediated at least in part via regulation of AKT signaling and FOXO1 expression. Using gene expression and bioinformatics analysis, together with functional screening, we identified several novel miR-486-5p target genes that may modulate erythroid differentiation. We further show that increased miR-486-5p expression in CML progenitors is related to both kinase-dependent and kinase-independent mechanisms. Inhibition of miR-486-5p reduced CML progenitor growth and enhanced apoptosis following imatinib treatment. In conclusion, our studies reveal a novel role for miR-486-5p in regulating normal hematopoiesis and of BCR-ABL-induced miR-486-5p overexpression in modulating CML progenitor growth, survival, and drug sensitivity.

Zou Y, Xiong H, Xiong H, et al.
A polysaccharide from mushroom Huaier retards human hepatocellular carcinoma growth, angiogenesis, and metastasis in nude mice.
Tumour Biol. 2015; 36(4):2929-36 [PubMed] Related Publications
Mushroom Huaier has become a focus of interest in the treatment of hepatocellular carcinoma (HCC). Presently, we isolated and purified one polysaccharide from this mushroom. This study aimed to investigate the effects of SP1 on tumor growth and metastasis in a HCC xenograft model and explore its possible mechanism of action. Our results showed that SP1 not only significantly inhibited the proliferation of SMMC-7721 cells in vitro at the concentration ranging from 0 to 800 μg/ml but also suppressed the HCC tumor growth and metastatic nodules to the lung in SMMC-7721-bearing mice by oral administration at three doses of 30, 60, and 120 mg/kg. Concomitantly, immunohistochemistry analysis of tumor tissues identified that SP1 administration at three doses significantly inhibited the in vivo cancer cell proliferation and microvessel density (MVD) formation, evidenced by a low proliferating cell nuclear antigen (PCNA) and CD34 expression, but increased the percentage of terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-positive cells. Keeping in line with this observation, SP1 treatment decreased serum matrix metalloproteinase (MMP) 2 and vascular endothelial growth factor (VEGF) levels, downregulated the protein expression of hypoxia-inducible factor (HIF)-1alpha, VEGF, MMP2, bcl-2, N-cadherin, signal transducer and activator of transcription 3 (STAT3), and metadherin (MTDH), and upregulated bax and NE-cadherin protein expression in tumor tissues. Taken together, our data suggest that SP1 appears to be a promising chemopreventive agent for the tumorigenesis and metastasis in patients with HCC, especially at advanced stages.

Ma SD, Xu X, Plowshay J, et al.
LMP1-deficient Epstein-Barr virus mutant requires T cells for lymphomagenesis.
J Clin Invest. 2015; 125(1):304-15 [PubMed] Article available free on PMC after 01/04/2016 Related Publications
Epstein-Barr virus (EBV) infection transforms B cells in vitro and is associated with human B cell lymphomas. The major EBV oncoprotein, latent membrane protein 1 (LMP1), mimics constitutively active CD40 and is essential for outgrowth of EBV-transformed B cells in vitro; however, EBV-positive diffuse large B cell lymphomas and Burkitt lymphomas often express little or no LMP1. Thus, EBV may contribute to the development and maintenance of human lymphomas even in the absence of LMP1. Here, we found that i.p. injection of human cord blood mononuclear cells infected with a LMP1-deficient EBV into immunodeficient mice induces B cell lymphomas. In this model, lymphoma development required the presence of CD4+ T cells in cord blood and was inhibited by CD40-blocking Abs. In contrast, LMP1-deficient EBV established persistent latency but did not induce lymphomas when directly injected into mice engrafted with human fetal CD34+ cells and human thymus. WT EBV induced lymphomas in both mouse models and did not require coinjected T cells in the cord blood model. Together, these results demonstrate that LMP1 is not essential for EBV-induced lymphomas in vivo and suggest that T cells supply signals that substitute for LMP1 in EBV-positive B cell lymphomagenesis.

Ségaliny AI, Mohamadi A, Dizier B, et al.
Interleukin-34 promotes tumor progression and metastatic process in osteosarcoma through induction of angiogenesis and macrophage recruitment.
Int J Cancer. 2015; 137(1):73-85 [PubMed] Related Publications
Interleukin-34 (IL-34) was recently characterized as the M-CSF "twin" cytokine, regulating the proliferation/differentiation/survival of myeloid cells. The implication of M-CSF in oncology was initially suspected by the reduced metastatic dissemination in knock-out mice, due to angiogenesis impairment. Based on this observation, our work studied the involvement of IL-34 in the pathogenesis of osteosarcoma. The in vivo effects of IL-34 were assessed on tissue vasculature and macrophage infiltration in a murine preclinical model based on a paratibial inoculation of human osteosarcoma cells overexpressing or not IL-34 or M-CSF. In vitro investigations using endothelial cell precursors and mature HUVEC cells were performed to analyse the involvement of IL-34 in angiogenesis and myeloid cell adhesion. The data revealed that IL-34 overexpression was associated with the progression of osteosarcoma (tumor growth, lung metastases) and an increase of neo-angiogenesis. In vitro analyses demonstrated that IL-34 stimulated endothelial cell proliferation and vascular cord formation. Pre-treatment of endothelial cells by chondroitinases/heparinases reduced the formation of vascular tubes and abolished the associated cell signalling. In addition, IL-34 increased the in vivo recruitment of M2 tumor-associated macrophages into the tumor tissue. IL-34 increased in vitro monocyte/CD34(+) cell adhesion to activated HUVEC monolayers under physiological shear stress conditions. This work also demonstrates that IL-34 is expressed by osteosarcoma cells, is regulated by TNF-α, IL-1β, and contributes to osteosarcoma growth by increasing the neo-angiogenesis and the recruitment of M2 macrophages. By promoting new vessel formation and extravasation of immune cells, IL-34 may play a key role in tumor development and inflammatory diseases.

Papp S, Dickson BC, Chetty R
Low-grade fibromyxoid sarcoma mimicking solitary fibrous tumor: a report of two cases.
Virchows Arch. 2015; 466(2):223-8 [PubMed] Related Publications
Low-grade fibromyxoid sarcoma (LGFMS) is an uncommon fibroblastic neoplasm with many morphologic mimics. Solitary fibrous tumor is a more common fibroblastic neoplasm, but the two rarely enter the same differential diagnosis. However, here, we report two unusual cases of LGFMS, containing dilated, hemangiopericytoma-like blood vessels, which prompted diagnostic considerations of solitary fibrous tumor. Both cases presented were confirmed to harbor FUS gene rearrangement, thereby confirming a diagnosis of LGFMS. One case is that of an 18-year-old male with a left forearm mass, and the other a 50-year-old man with a left popliteal mass. While both cases show some histologic features of LGFMS, the non-classical, dilated blood vessel pattern seen here may serve as a diagnostic pitfall, as LGFMS normally exhibits fine, curvilinear blood vessels. To our knowledge, there is only one other report of LGFMS displaying such hemangiopericytoma-like blood vessels. In summary, when encountering a bland spindle cell neoplasm with classic hemangiopericytoma-like blood vessels, it is prudent to consider a diagnosis of LGFMS besides solitary fibrous tumor--particularly in the absence of CD34 immunoreactivity as it may be a rare, mimicking variant of LGFMS.

Sinha S, Thomas D, Yu L, et al.
Mutant WT1 is associated with DNA hypermethylation of PRC2 targets in AML and responds to EZH2 inhibition.
Blood. 2015; 125(2):316-26 [PubMed] Article available free on PMC after 01/04/2016 Related Publications
Acute myeloid leukemia (AML) is associated with deregulation of DNA methylation; however, many cases do not bear mutations in known regulators of cytosine guanine dinucleotide (CpG) methylation. We found that mutations in WT1, IDH2, and CEBPA were strongly linked to DNA hypermethylation in AML using a novel integrative analysis of The Cancer Genome Atlas data based on Boolean implications, if-then rules that identify all individual CpG sites that are hypermethylated in the presence of a mutation. Introduction of mutant WT1 (WT1mut) into wild-type AML cells induced DNA hypermethylation, confirming mutant WT1 to be causally associated with DNA hypermethylation. Methylated genes in WT1mut primary patient samples were highly enriched for polycomb repressor complex 2 (PRC2) targets, implicating PRC2 dysregulation in WT1mut leukemogenesis. We found that PRC2 target genes were aberrantly repressed in WT1mut AML, and that expression of mutant WT1 in CD34(+) cord blood cells induced myeloid differentiation block. Treatment of WT1mut AML cells with short hairpin RNA or pharmacologic PRC2/enhancer of zeste homolog 2 (EZH2) inhibitors promoted myeloid differentiation, suggesting EZH2 inhibitors may be active in this AML subtype. Our results highlight a strong association between mutant WT1 and DNA hypermethylation in AML and demonstrate that Boolean implications can be used to decipher mutation-specific methylation patterns that may lead to therapeutic insights.

Xing X, Gu X, Ma T, Ye H
Biglycan up-regulated vascular endothelial growth factor (VEGF) expression and promoted angiogenesis in colon cancer.
Tumour Biol. 2015; 36(3):1773-80 [PubMed] Related Publications
Biglycan is an important component of the extracellular matrix, which belongs to the small leucine-rich proteoglycan family. Recent studies have shown that biglycan expression is elevated in many tumor tissues and implies poor prognosis, such as colon cancer. However, the molecular mechanism of biglycan in colon cancer has not been investigated. The present study aimed to investigate the effects of biglycan on vascular endothelial growth factor (VEGF) expression in colon cancer cells and on tumor angiogenesis in vivo. Biglycan overexpression vectors were constructed, and the stable biglycan overexpression in human colon cancer cell lines (HCT116 cells) was established by G418 screening. The stable cell clones were subsequently used to initiate tumor xenografts in nude mice. Our results showed that biglycan overexpression notably up-regulated the levels of VEGF in colon cancer cells, which was further confirmed by immunohistochemistry analysis in the xenograft colon tumors. Moreover, high levels of biglycan promoted angiogenesis and colon tumor growth, as evidenced by the increased cell viability, colon tumor size, and weight, as well as the CD34 expression. Additionally, we found that the extracellular signal-regulated kinase (ERK) signaling pathway was activated by biglycan in colon cancer cells. The ERK inhibitor PD98059 dramatically reversed the increased expression of VEGF induced by biglycan. Taken together, our results indicated that biglycan up-regulated VEGF expression in colon cancer cells and promoted tumor angiogenesis. Biglycan-mediated VEGF regulation may correlate with the activation of the ERK signaling pathway. Therefore, biglycan may be a promising target for anti-angiogenic therapy for cancer.

Matsushita H, Yahata T, Sheng Y, et al.
Establishment of a humanized APL model via the transplantation of PML-RARA-transduced human common myeloid progenitors into immunodeficient mice.
PLoS One. 2014; 9(11):e111082 [PubMed] Article available free on PMC after 01/04/2016 Related Publications
Recent advances in cancer biology have revealed that many malignancies possess a hierarchal system, and leukemic stem cells (LSC) or leukemia-initiating cells (LIC) appear to be obligatory for disease progression. Acute promyelocytic leukemia (APL), a subtype of acute myeloid leukemia characterized by the formation of a PML-RARα fusion protein, leads to the accumulation of abnormal promyelocytes. In order to understand the precise mechanisms involved in human APL leukemogenesis, we established a humanized in vivo APL model involving retroviral transduction of PML-RARA into CD34(+) hematopoietic cells from human cord blood and transplantation of these cells into immunodeficient mice. The leukemia well recapitulated human APL, consisting of leukemic cells with abundant azurophilic abnormal granules in the cytoplasm, which expressed CD13, CD33 and CD117, but not HLA-DR and CD34, were clustered in the same category as human APL samples in the gene expression analysis, and demonstrated sensitivity to ATRA. As seen in human APL, the induced APL cells showed a low transplantation efficiency in the secondary recipients, which was also exhibited in the transplantations that were carried out using the sorted CD34- fraction. In order to analyze the mechanisms underlying APL initiation and development, fractionated human cord blood was transduced with PML-RARA. Common myeloid progenitors (CMP) from CD34(+)/CD38(+) cells developed APL. These findings demonstrate that CMP are a target fraction for PML-RARA in APL, whereas the resultant CD34(-) APL cells may share the ability to maintain the tumor.

Zhu LY, Ren L, Ge Z, Li XB
Observation of microvessels and invasion in early colorectal neoplasms on narrow band imaging: combination with CD34 and matrix metalloproteinase-7 expression.
Eur J Gastroenterol Hepatol. 2014; 26(12):1428-33 [PubMed] Related Publications
OBJECTIVE: The study aims to clarify the role of narrow band imaging (NBI) in the prediction of invasion depth and the formation of lesion appearance under NBI with immunohistochemical analysis.
MATERIALS AND METHODS: As a prospective single-center study, Sano's classification of capillary pattern (CP) was applied to differentiate early colorectal neoplasms under NBI observation. Only lesions with CP type III were analyzed, compared with final histologic findings, and further immunohistochemical analysis with CD34 and matrix metalloproteinase-7 (MMP-7) was performed.
RESULTS: As for the 203 cases of CP type III lesions, the sensitivity, specificity, and accuracy for CP type IIIA/IIIB were, respectively, 88.4, 93.6, and 92.5% to differentiate high-grade neoplasia or slight submucosal invasive carcinoma from deep submucosal invasive carcinoma. NBI prediction for invasion depth corresponded to immunohistochemical outcomes of CD34 and MMP-7, which might explain the reason why CP type IIIB displays nearly avascular or loose microvascular areas on the lesion surface.
CONCLUSION: NBI is of excellent use in predicting invasion depth for early colorectal neoplasms, and positive expression of MMP-7 is associated with the appearance of CP type IIIB.

Sullivan HC, Edgar MA, Cohen C, et al.
The utility of ERG, CD31 and CD34 in the cytological diagnosis of angiosarcoma: an analysis of 25 cases.
J Clin Pathol. 2015; 68(1):44-50 [PubMed] Related Publications
AIMS: Erythroblast transformation specific related gene (ERG), a proto-oncogene member of the erythroblast transformation specific transcription factor family, is a sensitive marker of endothelial differentiation and is expressed in vascular tumours, including angiosarcomas (AS). Immunohistochemistry is necessary for the diagnosis of AS in fine needle aspirates where low cellularity and lack of preserved tissue architecture impedes diagnosis. The aim of this study was to assess the utility of an ERG-enriched immunohistochemistry panel in the cytological diagnosis of AS.
METHODS: 25 AS diagnosed on fine needle aspirates were stained for ERG, CD31, CD34, and AE1/AE3. Staining intensity and percentage tumour cell positivity were evaluated. Spearman's correlation was assessed for significant correlations between antibodies.
RESULTS: Sensitivities for ERG, CD31, CD34 and AE1/AE3 were 100%, 100%, 60% and 21%, respectively. Spearman's analysis revealed that ERG and CD31 staining correlated significantly; there was no significant correlation between CD31 and CD34 staining.
CONCLUSIONS: With equal sensitivity to, and strong correlation with CD31, ERG staining is highly suitable for the cytological diagnosis of AS. ERG and CD31 are more sensitive vascular markers than CD34. ERG, a nuclear stain, complements the cytoplasmic/membranous staining of CD31. Used in conjunction with CD31, ERG can corroborate the diagnosis of AS.

Eun JR, Jung YJ, Zhang Y, et al.
Hepatoma SK Hep-1 cells exhibit characteristics of oncogenic mesenchymal stem cells with highly metastatic capacity.
PLoS One. 2014; 9(10):e110744 [PubMed] Article available free on PMC after 01/04/2016 Related Publications
BACKGROUND: SK Hep-1 cells (SK cells) derived from a patient with liver adenocarcinoma have been considered a human hepatoma cell line with mesenchymal origin characteristics, however, SK cells do not express liver genes and exhibit liver function, thus, we hypothesized whether mesenchymal cells might contribute to human liver primary cancers. Here, we characterized SK cells and its tumourigenicity.
METHODS AND PRINCIPAL FINDINGS: We found that classical mesenchymal stem cell (MSC) markers were presented on SK cells, but endothelial marker CD31, hematopoietic markers CD34 and CD45 were negative. SK cells are capable of differentiate into adipocytes and osteoblasts as adipose-derived MSC (Ad-MSC) and bone marrow-derived MSC (BM-MSC) do. Importantly, a single SK cell exhibited a substantial tumourigenicity and metastatic capacity in immunodefficient mice. Metastasis not only occurred in circulating organs such as lung, liver, and kidneys, but also in muscle, outer abdomen, and skin. SK cells presented greater in vitro invasive capacity than those of Ad-MSC and BM-MSC. The xenograft cells from subcutaneous and metastatic tumors exhibited a similar tumourigenicity and metastatic capacity, and showed the same relatively homogenous population with MSC characteristics when compared to parental SK cells. SK cells could unlimitedly expand in vitro without losing MSC characteristics, its tumuorigenicity and metastatic capacity, indicating that SK cells are oncogenic MSC with enhanced self-renewal capacity. We believe that this is the first report that human MSC appear to be transformed into cancer stem cells (CSC), and that their derivatives also function as CSCs.
CONCLUSION: Our findings demonstrate that SK cells represent a transformation mechanism of normal MSC into an enhanced self-renewal CSC with metastasis capacity, SK cells and their xenografts represent a same relative homogeneity of CSC with substantial metastatic capacity. Thus, it represents a novel mechanism of tumor initiation, development and metastasis by CSCs of non-epithelial and endothelia origin.

Zhu MS, Xu LB, Zeng H, et al.
Association of Notch1 with vasculogenic mimicry in human hepatocellular carcinoma cell lines.
Int J Clin Exp Pathol. 2014; 7(9):5782-91 [PubMed] Article available free on PMC after 01/04/2016 Related Publications
BACKGROUND AND AIMS: According to recent findings, some tumor cells function as endothelial progenitor cells to initiate tumor vasculogenesis, known as "vasculogenic mimicry" (VM). Notch1, the key regulator of vasculogenesis and embryonic differentiation, has shown a correlation with a poor prognosis in hepatocellular carcinoma (HCC). We attempted to elucidate the relationship between Notch1 and the vascularization of HCC.
MATERIALS AND METHODS: HCC cell lines were assayed for tube formation and low-density lipoprotein (LDL) absorption. The translation level of targets of interest was verified using western blot. Notch1 was silenced in HepG2, BEL-7402 and HCCLM6 using lentivirus shRNA. A hypoxic culture was conducted in an anaerobic culture chamber to induce VM in HepG2. Samples from 53 patients with HCC, i.e., 5 with metastasis and 48 without were tested for Notch1(+) cells and CD34 negative plus Periodic Acid-Schiff (PAS) positive structures, respectively.
RESULTS: BEL-7402 and HCCLM6 were capable of tube formation and LDL absorption in vitro, while HepG2 was negative for both. Notch1 down-regulation suppressed endothelial marker expression and greatly impaired tube formation. After hypoxic culture, the tube formation capacity of HepG2 was significantly enhanced, along with an increase in Notch1 expression. Notch1 was strongly and profusely expressed in all 5 cases of distant metastasis, while 19 of the 48 cases without metastasis were sparsely positive (P < 0.05). Notch1 positivity was mainly seen in the cytoplasm and nuclei. VM structures were only found in 2 cases from the metastasis group (P < 0.05).
CONCLUSIONS: HCC is capable of VM. Notch1 might serve as a potential target for VM development in HCC.

Lavallée VP, Gendron P, Lemieux S, et al.
EVI1-rearranged acute myeloid leukemias are characterized by distinct molecular alterations.
Blood. 2015; 125(1):140-3 [PubMed] Article available free on PMC after 01/04/2016 Related Publications
The genetic and transcriptional signature of EVI1 (ecotropic viral integration site 1)-rearranged (EVI1-r) acute myeloid leukemias (AMLs) remains poorly defined. We performed RNA sequencing of 12 EVI1-r AMLs and compared the results with those of other AML subtypes (n = 139) and normal CD34(+) cells (n = 17). Results confirm high frequencies of RAS and other activated signaling mutations (10/12 AMLs) and identify new recurrent mutations in splicing factors (5/12 AMLs in SF3B1 and 2/12 AMLs in U2AF1), IKZF1 (3/12 AMLs), and TP53 (3/12 AMLs). Mutations in IKZF1, a gene located on chromosome 7, and monosomy 7 are mutually exclusive in this disease. Moreover IKZF1 expression is halved in monosomy 7 leukemias. EVI-r AMLs are also characterized by a unique transcriptional signature with high expression levels of MECOM, PREX2, VIP, MYCT1, and PAWR. Our results suggest that EVI1-r AMLs could be molecularly defined by specific transcriptomic anomalies and a hitherto unseen mutational pattern. Larger patient cohorts will better determine the frequency of these events.

Shirai T, Tsuchida S, Terauchi R, et al.
Primary pulmonary synovial sarcoma requiring differentiation from pulmonary metastasis of tibial adamantinoma: a case report.
BMC Res Notes. 2014; 7:736 [PubMed] Article available free on PMC after 01/04/2016 Related Publications
BACKGROUND: Primary pulmonary synovial sarcoma (PPSS) is rare. We describe a case of PPSS complicated by tibial adamantinoma that required differentiation from lung metastasis.
CASE PRESENTATION: A 39-year-old Japanese woman presented with hemoptysis, dyspnea, and a well-defined tumor measuring 3.0 cm in greatest diameter in the right lower lobe on chest computed tomography (CT). Positron emission tomography/CT with fluorodeoxyglucose (FDG-PET/CT) showed mild uptake of FDG (maximum standardized uptake value of 2.0). Her past history included surgery for adamantinoma of the right tibia at age 25 years. We considered the possibility of pulmonary metastasis from the adamantinoma and performed fluoroscopy-assisted thoracoscopic resection of the tumor after CT-guided Lipiodol marking. Histologically, the tumor was composed mainly of a dense proliferation of spindle cells. Immunohistochemical studies were positive for epithelial membrane antigen, B cell lymphoma 2, and transducing-like enhancer of split 1. They were negative for CD34. The synovial sarcoma, X breakpoint 1 gene-fusion transcript was detected by reverse transcription-polymerase chain reaction. It is diagnostic of PPSS. Resection margins were negative. The patient was well without evidence of recurrence or metastasis of the PPSS or adamantinoma at the 30-month and 15-year follow-ups.
CONCLUSION: Clinical and radiological manifestations of PPSS overlap with those of other lung tumors. The solitary pulmonary nodule in this case was indistinguishable from pulmonary metastases of the adamantinoma based on clinical symptoms, epidemiology, chest radiography, CT, and FDG-PET/CT. PPSS was diagnosed only after evaluating gross pathology, histology, immunohistochemistry, and cytogenetics. PPSS should be included in the differential diagnosis of a well-defined homogeneous round or oval lung mass. To our knowledge, this is the first report of PPSS complicated by adamantinoma.

Kim M, Tan YS, Cheng WC, et al.
MIR144 and MIR451 regulate human erythropoiesis via RAB14.
Br J Haematol. 2015; 168(4):583-97 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
Expression levels of MIR144 and MIR451 increase during erythropoiesis, a pattern that is conserved from zebrafish to humans. As these two miRs are expressed from the same polycistronic transcript, we manipulated MIR144 and MIR451 in human erythroid cells individually and together to investigate their effects on human erythropoiesis. Inhibition of endogenous human MIR451 resulted in decreased numbers of erythroid (CD71(hi) CD235a(hi) CD34(-) ) cells, consistent with prior studies in zebrafish and mice. In addition, inhibition of MIR144 impaired human erythroid differentiation, unlike in zebrafish and mouse studies where the functional effect of MIR144 on erythropoiesis was minimal. In this study, we found RAB14 is a direct target of both MIR144 and MIR451. As MIR144 and MIR451 expression increased during human erythropoiesis, RAB14 protein expression decreased. Enforced RAB14 expression phenocopied the effect of MIR144 and/or MIR451 depletion, whereas shRNA-mediated RAB14 knockdown protected cells from MIR144 and/or MIR451 depletion-mediated erythropoietic inhibition. RAB14 knockdown increased the frequency and number of erythroid cells, increased β-haemoglobin expression, and decreased CBFA2T3 expression during human erythropoiesis. In summary, we utilized MIR144 and MIR451 to identify RAB14 as a novel physiological inhibitor of human erythropoiesis.

Tursky ML, Beck D, Thoms JA, et al.
Overexpression of ERG in cord blood progenitors promotes expansion and recapitulates molecular signatures of high ERG leukemias.
Leukemia. 2015; 29(4):819-27 [PubMed] Related Publications
High expression of the ETS family transcription factor ERG is associated with poor clinical outcome in acute myeloid leukemia (AML) and acute T-cell lymphoblastic leukemia (T-ALL). In murine models, high ERG expression induces both T-ALL and AML. However, no study to date has defined the effect of high ERG expression on primary human hematopoietic cells. In the present study, human CD34+ cells were transduced with retroviral vectors to elevate ERG gene expression to levels detected in high ERG AML. RNA sequencing was performed on purified populations of transduced cells to define the effects of high ERG on gene expression in human CD34+ cells. Integration of the genome-wide expression data with other data sets revealed that high ERG drives an expression signature that shares features of normal hematopoietic stem cells, high ERG AMLs, early T-cell precursor-ALLs and leukemic stem cell signatures associated with poor clinical outcome. Functional assays linked this gene expression profile to enhanced progenitor cell expansion. These results support a model whereby a stem cell gene expression network driven by high ERG in human cells enhances the expansion of the progenitor pool, providing opportunity for the acquisition and propagation of mutations and the development of leukemia.

Mayer A, Schmidt M, Seeger A, et al.
GLUT-1 expression is largely unrelated to both hypoxia and the Warburg phenotype in squamous cell carcinomas of the vulva.
BMC Cancer. 2014; 14:760 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
BACKGROUND: Strongly increased uptake of glucose is a hallmark of solid malignant tumors. This phenotype can be triggered by hypoxia-induced gene expression changes or can occur independently of hypoxia as a consequence of malignant transformation itself, and is often referred to as the Warburg effect. The glycolytic phenotype has been associated with malignant progression and resistance to radio- and chemotherapy.
METHODS: We have chosen squamous cell carcinomas of the vulva (SCC-V) as a representative solid tumor entity to study the central players of this pathway, namely glucose transporter (GLUT)-1, carbonic anhydrase (CA) IX, hexokinase (HK)-2 and pyruvate kinase (PK)-M2, and have investigated their relationships to tumor microvessels (CD34, αSMA) and proliferation (Ki67). Expression of these proteins was analyzed in 38 SCC-Vs, 5 vulvar dysplasias and 10 non-neoplastic squamous epithelia of the vulva using multiparametric immunohistochemistry in registered serial sections (MIRSS).
RESULTS: Expression of GLUT-1 in invasive carcinomas was predominantly located in the outer layers of the tumor cell aggregates close to the vascularized tumor stroma, and only to a lesser extent colocalized with CA IX, which was repeatedly found at larger diffusion distances away from microvessels. CA IX expression was lower in invasive carcinomas compared to dysplasias and non-neoplastic tissue and higher in recurrent vs. primary tumors. Ki67-positive proliferating cells were partially colocalized with GLUT-1. However, HK-2 and PK-2--proteins centrally involved in the Warburg phenotype--did not show such a correlation.
CONCLUSIONS: Consistent with prior studies, the pattern of GLUT-1 clearly indicated that a large part of its expression is presumably unrelated to hypoxia. However, there was also no association with HK-2 and PK-M2, suggesting that the functional background of this expression is also independent of aerobic glycolysis. CA IX may be worth consideration as a marker of biological hypoxia, as should its pathophysiological consequences in SCC-V.

Wang XW, Cai CL, Xu JM, et al.
Increased expression of chitinase 3-like 1 is a prognosis marker for non-small cell lung cancer correlated with tumor angiogenesis.
Tumour Biol. 2015; 36(2):901-7 [PubMed] Related Publications
Increasing evidence demonstrated that chitinase 3-like 1 (CHI3L1) was highly expressed and tightly associated with human tumor development and progression. However, its precise role in non-small cell lung cancer (NSCLC) remains to be delineated. The aim of this study was to examine CHI3L1 expression in patients with NSCLC and explore the relationship of CHI3L1 protein with clinicopathologic factors, tumor angiogenesis, and prognosis. CHI3L1 protein and intratumoral microvessels were examined by immunohistochemical staining in 95 NSCLC patients. Intratumoral microvessel density (MVD) was measured by counting CD34-positive immunostained endothelial cells. Quantitative real-time PCR (qRT-PCR) analyses were used to investigate the CHI3L1 expression status in tissues. Our result showed that CHI3L1 was significantly up-regulated in NSCLC tissues. In addition, univariate and multivariate analysis demonstrated that CHI3L1 protein overexpression and high MVD were significantly associated with tumor relapse. Although CHI3L1 overexpression and high MVD indicated poor overall survival (P < 0.05), multivariate analysis suggested that only CHI3L1 overexpression was an independent prognostic marker for unfavorable overall survival in patients with NSCLC (P < 0.05). The current results demonstrated that CHI3L1 may be a promising biomarker to identify individuals with poor prognostic potential and a possible target for anti-angiogenic therapy in patients with early stage NSCLC.

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