CTSL

Gene Summary

Gene:CTSL; cathepsin L
Aliases: MEP, CATL, CTSL1
Location:9q21.33
Summary:The protein encoded by this gene is a lysosomal cysteine proteinase that plays a major role in intracellular protein catabolism. Its substrates include collagen and elastin, as well as alpha-1 protease inhibitor, a major controlling element of neutrophil elastase activity. The encoded protein has been implicated in several pathologic processes, including myofibril necrosis in myopathies and in myocardial ischemia, and in the renal tubular response to proteinuria. This protein, which is a member of the peptidase C1 family, is a dimer composed of disulfide-linked heavy and light chains, both produced from a single protein precursor. Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Apr 2012]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:cathepsin L1
Source:NCBIAccessed: 15 March, 2017

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 (1992-2017)
Graph generated 15 March 2017 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 15 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (8)

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: CTSL (cancer-related)

Ohno Y, Kitamura H, Takahashi N, et al.
IL-6 down-regulates HLA class II expression and IL-12 production of human dendritic cells to impair activation of antigen-specific CD4(+) T cells.
Cancer Immunol Immunother. 2016; 65(2):193-204 [PubMed] Related Publications
Immunosuppression in tumor microenvironments critically affects the success of cancer immunotherapy. Here, we focused on the role of interleukin (IL)-6/signal transducer and activator of transcription (STAT3) signaling cascade in immune regulation by human dendritic cells (DCs). IL-6-conditioned monocyte-derived DCs (MoDCs) impaired the presenting ability of cancer-related antigens. Interferon (IFN)-γ production attenuated by CD4(+) T cells co-cultured with IL-6-conditioned MoDCs corresponded with decreased DC IL-12p70 production. Human leukocyte antigen (HLA)-DR and CD86 expression was significantly reduced in CD11b(+)CD11c(+) cells obtained from peripheral blood mononuclear cells (PBMCs) of healthy donors by IL-6 treatment and was STAT3 dependent. Arginase-1 (ARG1), lysosomal protease, cathepsin L (CTSL), and cyclooxygenase-2 (COX2) were involved in the reduction of surface HLA-DR expression. Gene expressions of ARG1, CTSL, COX2, and IL6 were higher in tumor-infiltrating CD11b(+)CD11c(+) cells compared with PBMCs isolated from colorectal cancer patients. Expression of surface HLA-DR and CD86 on CD11b(+)CD11c(+) cells was down-regulated, and T cell-stimulating ability was attenuated compared with PBMCs, suggesting that an immunosuppressive phenotype might be induced by IL-6, ARG1, CTSL, and COX2 in tumor sites of colorectal cancer patients. There was a relationship between HLA-DR expression levels in tumor tissues and the size of CD4(+) T and CD8(+) T cell compartments. Our findings indicate that IL-6 causes a dysfunction in human DCs that activates cancer antigen-specific Th cells, suggesting that blocking the IL-6/STAT3 signaling pathway might be a promising strategy to improve cancer immunotherapy.

Sudhan DR, Pampo C, Rice L, Siemann DW
Cathepsin L inactivation leads to multimodal inhibition of prostate cancer cell dissemination in a preclinical bone metastasis model.
Int J Cancer. 2016; 138(11):2665-77 [PubMed] Free Access to Full Article Related Publications
It is estimated that approximately 90% of patients with advanced prostate cancer develop bone metastases; an occurrence that results in a substantial reduction in the quality of life and a drastic worsening of prognosis. The development of novel therapeutic strategies that impair the metastatic process and associated skeletal adversities is therefore critical to improving prostate cancer patient survival. Recognition of the importance of Cathepsin L (CTSL) to metastatic dissemination of cancer cells has led to the development of several CTSL inhibition strategies. The present investigation employed intra-cardiac injection of human PC-3ML prostate cancer cells into nude mice to examine tumor cell dissemination in a preclinical bone metastasis model. CTSL knockdown confirmed the validity of targeting this protease and subsequent intervention studies with the small molecule CTSL inhibitor KGP94 resulted in a significant reduction in metastatic tumor burden in the bone and an improvement in overall survival. CTSL inhibition by KGP94 also led to a significant impairment of tumor initiated angiogenesis. Furthermore, KGP94 treatment decreased osteoclast formation and bone resorptive function, thus, perturbing the reciprocal interactions between tumor cells and osteoclasts within the bone microenvironment which typically result in bone loss and aggressive growth of metastases. These functional effects were accompanied by a significant downregulation of NFκB signaling activity and expression of osteoclastogenesis related NFκB target genes. Collectively, these data indicate that the CTSL inhibitor KGP94 has the potential to alleviate metastatic disease progression and associated skeletal morbidities and hence may have utility in the treatment of advanced prostate cancer patients.

Mori J, Tanikawa C, Funauchi Y, et al.
Cystatin C as a p53-inducible apoptotic mediator that regulates cathepsin L activity.
Cancer Sci. 2016; 107(3):298-306 [PubMed] Free Access to Full Article Related Publications
In response to various cellular stresses, p53 is activated and inhibits malignant transformation through the transcriptional regulation of its target genes. However, the full picture of the p53 downstream pathway still remains to be elucidated. Here we identified cystatin C, a major inhibitor of cathepsins, as a novel p53 target. In response to DNA damage, activated p53 induced cystatin C expression through p53 binding sequence in the first intron. We showed that cathepsin L activity was decreased in HCT116 p53(+/+) cells after adriamycin treatment, but not in HCT116 p53(-/-) cells. We also found that knockdown of cystatin C reduced adriamycin-induced caspase-3 activation. Cystatin C expression was significantly downregulated in breast cancer cells with p53 mutations, and decreased cystatin C expression was associated with poor prognosis of breast cancer. Our findings revealed an important role of the p53-cystatin C pathway in human carcinogenesis.

Hassan AE, Abou-Elkhair RA, Parker WB, et al.
6-Methylpurine derived sugar modified nucleosides: Synthesis and in vivo antitumor activity in D54 tumor expressing M64V-Escherichia coli purine nucleoside phosphorylase.
Eur J Med Chem. 2016; 108:616-22 [PubMed] Related Publications
Impressive antitumor activity has been observed with fludarabine phosphate against tumors that express Escherichia coli purine nucleoside phosphorylase (PNP) due to the liberation of 2-fluoroadenine in the tumor tissue. 6-Methylpurine (MeP) is another cytotoxic adenine analog that does not exhibit selectivity when administered systemically, and could be very useful in a gene therapy approach to cancer treatment involving E. coli PNP. The prototype MeP releasing prodrug 9-(2-deoxy-β-d-ribofuranosyl)-6-methylpurine (1) [MeP-dR] has demonstrated good activity against tumors expressing E. coli PNP, but its antitumor activity is limited due to toxicity resulting from the generation of MeP from gut bacteria. Therefore, we have embarked on a medicinal chemistry program to identify a combination of non-toxic MeP prodrugs and non-human adenosine glycosidic bond cleaving enzymes. The two best MeP-based substrates with M64V-E coli PNP, a mutant which was engineered to tolerate modification at the 5'-position of adenosine and its analogs, were 9-(6-deoxy-α-l-talofuranosyl)-6-methylpurine (3) [methyl(talo)-MeP-R] and 9-(α-l-lyxofuranosyl)6-methylpurine (4) [lyxo-MeP-R]. The detailed synthesis methyl(talo)-MeP-R and lyxo-MeP-R, and the evaluation of their substrate activity with 4 enzymes not normally associated with cancer patients is described. In addition, we have determined the intraperitoneal pharmacokinetic (ip-PK) properties of methyl(talo)-MeP-R and have determined its in vivo bystander activity in mice bearing D54 tumors that express M64V PNP. The observed good in vivo bystander activity of [methyl(talo)-MeP-R/M64V-E coli PNP combination suggests that these agents could be useful for the treatment of cancer.

Wang W, Long L, Wang L, et al.
Knockdown of Cathepsin L promotes radiosensitivity of glioma stem cells both in vivo and in vitro.
Cancer Lett. 2016; 371(2):274-84 [PubMed] Related Publications
The presence of glioma stem cells (GSCs) in tumor is relevant for glioma treatment resistance. This study assessed whether knockdown of Cathepsin L can influence GSC growth, tumor radiosensitivity, and clinical outcome. Protein levels of Cathepsin L and stem cell markers (CD133 and Nestin) were analyzed in samples from 90 gliomas of different WHO grades and 6 normal brain tissues by immunohistochemistry. Two glioma stem cell lines with overexpressed Cathepsin L were stably transfected with Cathepsin L short hairpin RNA expression vectors. The effects of Cathepsin L inhibition on radiosensitivity, self-renewal, stemness, DNA damage, and apoptosis were evaluated. In addition, an intracranial animal model and subcutaneous tumor xenografts in nude mice were used to assess tumor response to Cathepsin L inhibition in vivo. Our results proved that expressions of Cathepsin L and CD133, but not of Nestin, correlated with malignant grades of glioma tissues. GSCs with high Cathepsin L and CD133 co-expression were extraordinarily radioresistant. Cathepsin L inhibition with radiotherapy significantly reduced GSC growth, promoted apoptosis, and improved radiosensitivity. Knockdown of Cathepsin L resulted in a dramatic reduction of CD133 expression, as well as the decreased phosphorylation of DNA repair checkpoint proteins (ATM and DNA-PKcs). Furthermore, combination of Cathepsin L inhibition and radiotherapy potently blocked tumor growth and decreased blood vessel formation in vivo. Taken together, these findings suggest Cathepsin L as a promising therapeutic target for clinical therapy in GBM patients.

Berardi DE, Flumian C, Campodónico PB, et al.
Myoepithelial and luminal breast cancer cells exhibit different responses to all-trans retinoic acid.
Cell Oncol (Dordr). 2015; 38(4):289-305 [PubMed] Related Publications
PURPOSE: Breast cancer is the leading cause of death among women worldwide. The exact role of luminal epithelial (LEP) and myoephitelial (MEP) cells in breast cancer development is as yet unclear, as also how retinoids may affect their behaviour. Here, we set out to evaluate whether retinoids may differentially regulate cell type-specific processes associated with breast cancer development using the bi-cellular LM38-LP murine mammary adenocarcinoma cell line as a model.
MATERIALS AND METHODS: The bi-cellular LM38-LP murine mammary cell line was used as a model throughout all experiments. LEP and MEP subpopulations were separated using inmunobeads, and the expression of genes known to be involved in epithelial to mysenchymal transition (EMT) was assessed by qPCR after all-trans retinoic acid (ATRA) treatment. In vitro invasive capacities of LM38-LP cells were evaluated using 3D Matrigel cultures in conjunction with confocal microscopy. Also, in vitro proliferation, senescence and apoptosis characteristics were evaluated in the LEP and MEP subpopulations after ATRA treatment, as well as the effects of ATRA treatment on the clonogenic, adhesive and invasive capacities of these cells. Mammosphere assays were performed to detect stem cell subpopulations. Finally, the orthotopic growth and metastatic abilities of LM38-LP monolayer and mammosphere-derived cells were evaluated in vivo.
RESULTS: We found that ATRA treatment modulates a set of genes related to EMT, resulting in distinct gene expression signatures for the LEP or MEP subpopulations. We found that the MEP subpopulation responds to ATRA by increasing its adhesion to extracellular matrix (ECM) components and by reducing its invasive capacity. We also found that ATRA induces apoptosis in LEP cells, whereas the MEP compartment responded with senescence. In addition, we found that ATRA treatment results in smaller and more organized LM38-LP colonies in Matrigel. Finally, we identified a third subpopulation within the LM38-LP cell line with stem/progenitor cell characteristics, exhibiting a partial resistance to ATRA.
CONCLUSIONS: Our results show that the luminal epithelial (LEP) and myoephitelial (MEP) mammary LM38-P subpopulations respond differently to ATRA, i.e., the LEP subpopulation responds with increased cell cycle arrest and apoptosis and the MEP subpopulation responds with increased senescence and adhesion, thereby decreasing its invasive capacity. Finally, we identified a third subpopulation with stem/progenitor cell characteristics within the LM38-LP mammary adenocarcinoma cell line, which appears to be non-responsive to ATRA.

Merhi A, De Mees C, Abdo R, et al.
Wnt/β-Catenin Signaling Regulates the Expression of the Ammonium Permease Gene RHBG in Human Cancer Cells.
PLoS One. 2015; 10(6):e0128683 [PubMed] Free Access to Full Article Related Publications
Ammonium is a metabolic waste product mainly detoxified by the liver. Hepatic dysfunction can lead to cytotoxic accumulation of circulating ammonium and to subsequent encephalopathy. Transmembrane ammonium transport is a widely spread process ensured by the highly conserved proteins of the Mep-Amt-Rh superfamily, including the mammalian Rhesus (Rh) factors. The regulatory mechanisms involved in the control of RH genes expression remain poorly studied. Here we addressed the expression regulation of one of these factors, RHBG. We identify HepG2 hepatocellular carcinoma cells and SW480 colon adenocarcinoma cells as expressing RHBG and show that its expression relies on β-catenin signaling. siRNA-mediated β-catenin knockdown resulted in significant reduction of RHBG mRNA in both cell lines. Pharmaceutical inhibition of the TCF4/β-catenin interaction or knockdown of the transcription factor TCF4 also downregulated RHBG expression. We identify a minimal RHBG regulatory sequence displaying a promoter activity and show that β-catenin and TCF4 bind to this fragment in vivo. We finally characterize the role of potential TCF4 binding sites in RHBG regulation. Taken together, our results indicate RHBG expression as a direct target of β-catenin regulation, a pathway frequently deregulated in many cancers and associated with tumorigenesis.

Tholen M, Wolanski J, Stolze B, et al.
Stress-resistant Translation of Cathepsin L mRNA in Breast Cancer Progression.
J Biol Chem. 2015; 290(25):15758-69 [PubMed] Free Access to Full Article Related Publications
The cysteine protease cathepsin L (CTSL) is often thought to act as a tumor promoter by enhancing tumor progression and metastasis. This goes along with increased CTSL activity in various tumor entities; however, the mechanisms leading to high CTSL levels are incompletely understood. With the help of the polyoma middle T oncogene driven breast cancer mouse model expressing a human CTSL genomic transgene, we show that CTSL indeed promotes breast cancer metastasis to the lung. During tumor formation and progression high expression levels of CTSL are maintained by enduring translation of CTSL mRNA. Interestingly, human breast cancer specimens expressed the same pattern of 5' untranslated region (UTR) splice variants as the transgenic mice and the human cancer cell line MDA-MB 321. By polyribosome profiling of tumor tissues and human breast cancer cells, we observe an intrinsic resistance of CTSL to stress-induced shutdown of translation. This ability can be attributed to all 5' UTR variants of CTSL and is not dependent on a previously described internal ribosomal entry site motif. In conclusion, we provide in vivo functional evidence for overexpressed CTSL as a promoter of lung metastasis, whereas high CTSL levels are maintained during tumor progression due to stress-resistant mRNA translation.

You L, Wang Z, Li H, et al.
The role of STAT3 in autophagy.
Autophagy. 2015; 11(5):729-39 [PubMed] Free Access to Full Article Related Publications
Autophagy is an evolutionarily conserved process in eukaryotes that eliminates harmful components and maintains cellular homeostasis in response to a series of extracellular insults. However, these insults may trigger the downstream signaling of another prominent stress responsive pathway, the STAT3 signaling pathway, which has been implicated in multiple aspects of the autophagic process. Recent reports further indicate that different subcellular localization patterns of STAT3 affect autophagy in various ways. For example, nuclear STAT3 fine-tunes autophagy via the transcriptional regulation of several autophagy-related genes such as BCL2 family members, BECN1, PIK3C3, CTSB, CTSL, PIK3R1, HIF1A, BNIP3, and microRNAs with targets of autophagy modulators. Cytoplasmic STAT3 constitutively inhibits autophagy by sequestering EIF2AK2 as well as by interacting with other autophagy-related signaling molecules such as FOXO1 and FOXO3. Additionally, the mitochondrial translocation of STAT3 suppresses autophagy induced by oxidative stress and may effectively preserve mitochondria from being degraded by mitophagy. Understanding the role of STAT3 signaling in the regulation of autophagy may provide insight into the classic autophagy model and also into cancer therapy, especially for the emerging targeted therapy, because a series of targeted agents execute antitumor activities via blocking STAT3 signaling, which inevitably affects the autophagy pathway. Here, we review several of the representative studies and the current understanding in this particular field.

Ruan J, Zheng H, Fu W, et al.
Increased expression of cathepsin L: a novel independent prognostic marker of worse outcome in hepatocellular carcinoma patients.
PLoS One. 2014; 9(11):e112136 [PubMed] Free Access to Full Article Related Publications
OBJECTIVES: To investigate the expression and role of Cathepsin L (CTSL) in Hepatocellular carcinoma (HCC) tissue and cell line (MHCC-97H), and to evaluate the clinical and prognostic significance of CTSL protein in patients with HCC.
METHODS: The expression of CTSL was examined in HCC tissue and MHCC-97H cells by Western-blotting, Real-time PCR and immunohistochemical staining. Cell growth curve assay and colony formation assay were used to verify the effect of CTSL on the proliferation and tumor progression ability of MHCC-97H cells. Tumor formation assay in nude mice was used to analyze the effect of CTSL on the tumorigenicity of MHCC-97H cells.
RESULTS: The status of CTSL protein in carcinoma tissues is much higher than that in paracarcinoma tissues. The overall survival of the patients with high CTSL expression was significantly shorter than the low CTSL expression group. high CTSL expression was significantly correlated with advanced clinical staging, histological grade and tumor recurrence. In vitro experiments demonstrated that over-expression of CTSL in MHCC-97H cells promoted cell proliferation and tumor progression ability. Down-regulation of CTSL showed the opposite effects. Over-expression of CTSL increase the tumorigenicity of MHCC-97H cells by in vivo experiments. Moreover, multivariate analysis suggested that CTSL expression might be an independent prognostic indicator for the survival of HCC patients after curative surgery.
CONCLUSIONS: CTSL might involve in the development and progression of HCC as a oncogene, and thereby may be a valuable prognostic marker for HCC patients.

Mariş D, Nica D, Mohan D, et al.
Multidisciplinary management of adult low grade gliomas.
Chirurgia (Bucur). 2014 Sep-Oct; 109(5):590-9 [PubMed] Related Publications
BACKGROUND: Adult hemispheric low grade gliomas (LGG) cover a pathologic spectrum which has specific clinical, histological and molecular characteristics. The optimal management of these tumors is still a controversial topic in international literature.
METHODS: We evaluated scientific papers from the literature (Medline and Cochrane Library to date) and we compared the results found there with our experience, trying to create a pattern of treatment of our own.
RESULTS AND CONCLUSIONS: The advances in microsurgical and neuromonitoring techniques, as well as in neuroimaging, allow for a more aggressive resection of LGG with a significant improvement in overall survival and quality of life. The potential risks of the "wait and see" policy and the neurotoxicity of radiotherapy are challenged by the benefits of careful surgical resection and up-front chemotherapy. The present day treatment strategy, based on recent evidence, should include a maximal surgical resection when possible, with the full preservation of the patients ability, and delayed radiotherapy. The role of temozolomide in the management of LGG and the identification of the therapeutic modality with the best quality of life profile will be determined by ongoing trials. The further characterization of prognostic relevance of molecular markers and data from advanced imaging techniques needs an intensification of research and validation efforts.
ABBREVIATIONS: LGG: low grade gliomas, WHO: World Health Organization, OS: overall survival, PFS: progression-free survival, MRI: Magnetic resonance imaging, MRS: Magnetic resonance spectroscopy, MPFS: malignant progression-free survival, rCBV: Relative Cerebral Blood Volume, QOL: quality of life, FLAIR: Fluid attenuated inversion recovery, MGMT: O6-methylguanine DNA methyltransferase enzyme, DSC MR imaging: Dynamic Susceptibility Contrast Perfusion MR imaging, 1H-MRS: Proton Magnetic Resonance Spectroscopy, IDH1: isocitrate dehydrogenase 1 gene, SPECT: Single-photon emission computed tomography, PET: Positron emission tomography, DTI-FT: Diffuse Tensor Imaging-fiber tracking technique, DES: direct electrical stimulation, EEG: Electroencephalography, EcoG: Electrocorticography, MEP: motor evoked potentials, EMG: Electromyography, AED: anti-epileptic drugs, TMZ: Temozolomide, EORTC: European Organization for Research and Treatment of Cancer, NCCTG: North Central Cancer Treatment Group, RTOG: Radiation Therapy Oncology Group, ECOG: Eastern Cooperative Oncology Group, EOR: extent of resection, Gy: Gray (unit), GyE: gray equivalent, RT: radiation therapy, IMRT: image-guided intensity modulated radiotherapy, FSRT: fractionated stereotactic radiotherapy, SRS: proton therapy or stereotactic radiosurgery, LET: high-linear energy transfer beams, RBE: relative biological effectiveness, CTCAE: Common Terminology Criteria for Adverse Events, PCV: procarbazine, lomustine, and vincristine chemotherapy.

Zhang L, Wei L, Shen G, et al.
Cathepsin L is involved in proliferation and invasion of ovarian cancer cells.
Mol Med Rep. 2015; 11(1):468-74 [PubMed] Related Publications
Cathepsin L (CTSL) is a lysosomal cysteine protease that has been found to be overexpressed in ovarian cancer (OC). The aim of the present study was to investigate the possible involvement of CTSL in the development of OC. In this study, RNA interference with a CTSL small hairpin RNA (CTSL-shRNA), and a plasmid carrying CTSL were used to identify the effects of this enzyme on the regulation of the malignant behavior of OC cells. OV-90 and SKOV3 human ovarian cancer cell lines were selected as cell models in vitro and in vivo. The results showed that downregulation of CTSL significantly inhibits the proliferative and invasive capability of SKOV3 cells, and that upregulation of CTSL in OV-90 cells leads to opposite effects. Compared with parental OC cells, cells in which CTSL was silenced exhibited a reduced capacity to develop into tumors in nude mice, while the growth of tumor xenografts derived from these cells was markedly constrained. In conclusion, the results suggested that CTSL contributes to the proliferation and metastasis of OC, and that CTSL may be a novel molecular target for OC treatment.

Skinner HD, Lee JH, Bhutani MS, et al.
A validated miRNA profile predicts response to therapy in esophageal adenocarcinoma.
Cancer. 2014; 120(23):3635-41 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: In the current study we present a validated miRNA signature to predict pathologic complete response (pCR) to neoadjuvant chemoradiation in esophageal adenocarcinoma.
METHODS: Three patient cohorts (discovery, n = 10; model, n = 43; and validation, n = 65) with locally advanced esophageal adenocarcinoma were analyzed. In the discovery cohort 754 miRNAs were examined in pretreatment tumor biopsy specimens using a TaqMan array. Of these, the 44 most significantly altered between tumors with pCR and non-pCR were examined in an additional 43 tumors using a Fluidigm 48.48 array. The 4 miRNAs (mir-505*, mir-99b, mir-451, and mir-145*) significantly predicting pCR in both cohorts were examined in an additional validation cohort (n = 65) using an Illumina array. These 4 miRNAs were used to generate an miRNA expression profile (MEP) score.
RESULTS: The 4 miRNAs profiled are highly significantly associated with pCR in the model cohort (Ptrend  = .008), the validation cohort (Ptrend  = .025), and the combined cohort (Ptrend  = 4.6 × 10(-4) ). The receiver-operator characteristic areas under the curves (AUCs) for the MEP score were 0.78 for the model cohort, 0.71 for the validation cohort, and 0.72 for the combined cohort. When combined with clinical variables, the MEP score AUCs increased to 0.89, 0.77, and 0.81, respectively Estimates from logistic regression based on the MEP were determined and used to generate a probability of pCR plot, which identifies a group of patients with very high (≥80%) and very low (≤10%) probability of pCR.
CONCLUSIONS: The MEP score provides a validated means of predicting pCR to neoadjuvant chemoradiotherapy in esophageal adenocarcinoma that is robust across several analysis platforms.

Huang PC, Li WF, Liao PC, et al.
Risk for estrogen-dependent diseases in relation to phthalate exposure and polymorphisms of CYP17A1 and estrogen receptor genes.
Environ Sci Pollut Res Int. 2014; 21(24):13964-73 [PubMed] Related Publications
Evidence has shown that polymorphisms of various genes known to be involved in estrogen biosynthesis and function are associated with estrogen-dependent diseases (EDDs). These genes include CYP17A1, estrogen receptor 1 (ESR1), and 2 (ESR2). Phthalates are considered estrogenic endocrine disruptors, and recent research has suggested that they may act as a risk factor for EDDs. However, extremely few studies have assessed the effects of gene-environment interaction on these diseases. We recruited 44 patients with endometriosis or adenomyosis, 36 patients with leiomyoma, and 69 healthy controls from a medical center in Taiwan between 2005 and 2007. Urine samples were collected and analyzed for seven phthalate metabolites using liquid chromatography tandem mass spectrometry. Peripheral lymphocytes were used for DNA extraction to determine the genotype of CYP17A1, ESR1, and ESR2. Compared to controls, patients with leiomyoma had significantly higher levels of total urinary mono-ethylhexyl phthalate (ΣMEHP) (52.1 vs. 29.6 μg/g creatinine, p = 0.040), mono-n-butyl phthalate (MnBP) (75.4 vs. 51.3 μg/g creatinine, p = 0.019), and monoethyl phthalate (MEP) (103.7 vs. 59.3 μg/g creatinine, p = 0.031). In contrast, patients with endometriosis or adenomyosis showed a marginally increased level of urinary MEHP only. Subjects who were homozygous for both the ESR1 C allele (rs2234693) and CYP17A1 C allele (rs743572) showed a significantly increased risk for leiomyoma (OR = 19.8; 95 % CI, 1.70; 231.5; p = 0.017) relative to subjects with other genotypes of ESR1 and CYP17A1. These results were obtained after adjusting for age, cigarette smoking, MEHP level, GSTM1 genotype and other covariates. Our results suggested that both CYP17A1 and ESR1 polymorphisms may modulate the effects of phthalate exposure on the development of leiomyoma.

Subimerb C, Wongkham C, Khuntikeo N, et al.
Transcriptional profiles of peripheral blood leukocytes identify patients with cholangiocarcinoma and predict outcome.
Asian Pac J Cancer Prev. 2014; 15(10):4217-24 [PubMed] Related Publications
Cholangiocarcinoma (CCA), a slow growing but highly metastatic tumor, is highly prevalent in Northeast Thailand. Specific tests that predict prognosis of CCA remain elusive. The present study was designed to investigate whether peripheral blood leukocyte (PBL) transcriptional profiles might be of use as a prognostic test in CCA patients. Gene expression profiles of PBLs from 9 CCA and 8 healthy subjects were conducted using the Affymetrix HG_U133 Plus 2.0 GeneChip. We indentified informative PBLs gene expression profiles that could reliably distinguish CCA patients from healthy subjects. Of these CCA specific genes, 117 genes were up regulated and 60 were down regulated. The molecular and cellular functions predicted for these CCA specific genes according to the Gene Ontology database indicated differential PBL expression of host immune response and tumor progression genes (EREG, TGF β1, CXCL2, CXCL3, IL-8, and VEGFA). The expression levels of 9 differentially expressed genes were verified in 36 CCA vs 20 healthy subjects. A set of three tumor invasion related genes (PLAU, CTSL and SERPINB2) computed as "prognostic index" was found to be an independent and statistically significant predictor for CCA patient survival. The present study shows that CCA PBLs may serve as disease predictive clinically accessible surrogates for indentifying expressed genes reflective of CCA disease severity.

Gong J, Zhang H, Xing S, et al.
High expression levels of CXCL12 and CXCR4 predict recurrence of adamanti-nomatous craniopharyngiomas in children.
Cancer Biomark. 2014; 14(4):241-51 [PubMed] Related Publications
BACKGROUND: Adamantinomatous craniopharyngioma (ACP) is a benign but maldevelopmental tumor with a high recurrence rate.
OBJECTIVE: Theaim of this study was to investigate the dysregulated biological molecules that play important roles in the recurrence of ACP.
METHODS: We first performed microarray analysis on tumor samples from two pediatric patients with recurrent ACP and from two pediatric ACP patients without recurrence after a one-year follow-up. The expression of CXCL12 and CXCR4 in 45 specimens of pediatric ACP was further evaluated by immunohistochemistry. These results were correlated with the clinicopathological parameters and survival of the patients.
RESULTS: Four downregulated genes (APC, ITGA, MCAM, and TIMP4) and 16 upregulated genes (CST7, CTSK, CTSL1, CXCL12, CXCR4, FN1, FXYD5, ITGB3, MMP2, MMP3, MMP7, MMP9, NR4A3, PLAUR, TIMP2, and VEGFA) were found in the recurrent patients. CXCL12 and CXCR4 were highly expressed in 13 patients (28.9%) and 14 patients (31.1%), respectively. High levels of CXCL12 and CXCR4 expression were significantly associated with a poor recurrence-free survival and were the prognostic factors for ACP recurrence in pediatric patients.
CONCLUSIONS: High levels of CXCL12 and CXCR4 expression were associated with ACP recurrence. The role of CXCL12 and CXCR4 in the development of brain tumors requires further research.

Dautzenberg IJ, van den Wollenberg DJ, van den Hengel SK, et al.
Mammalian orthoreovirus T3D infects U-118 MG cell spheroids independent of junction adhesion molecule-A.
Gene Ther. 2014; 21(6):609-17 [PubMed] Related Publications
In the canonical pathway, infection of cells by the wild-type mammalian orthoreovirus Type 3 Dearing (T3D) is dependent on the interaction of the viral spike protein σ1 with the high-affinity cellular receptor junction adhesion molecule-A (JAM-A). We previously demonstrated that the human glioblastoma cell line U-118 MG does not express JAM-A and resists reovirus T3D infection in standard cell culture conditions (SCCC). Heterologous JAM-A expression sensitises U-118 MG cells to reovirus T3D. Here we studied reovirus infection in U-118 MG cells grown in spheroid cultures with the premise that cells in such cultures resemble cells in tumours more than those grown under standard adherent cell culture conditions on a plastic surface. Although the U-118 MG cells in spheroids do not express JAM-A, they are susceptible to reovirus T3D infection. We show that this can be attributed to factors secreted by cells in the spheroids. The concentration of active extracellular proteases cathepsin B and L in the medium of spheroid cultures was increased 19- and 24-fold, respectively, as compared with SCCC. These enzymes can convert the reovirus particles into a form that can infect the U-118 MG cells independent of JAM-A. Taken together, these data demonstrate that infection of tumour cells by wild-type reovirus T3D is not strictly dependent on the expression of JAM-A on the cell surface.

Ueki N, Lee S, Sampson NS, Hayman MJ
Selective cancer targeting with prodrugs activated by histone deacetylases and a tumour-associated protease.
Nat Commun. 2013; 4:2735 [PubMed] Related Publications
Eradication of cancer cells while minimizing damage to healthy cells is a primary goal of cancer therapy. Highly selective drugs are urgently needed. Here we demonstrate a new prodrug strategy for selective cancer therapy that utilizes increased histone deacetylase (HDAC) and tumour-associated protease activities produced in malignant cancer cells. By coupling an acetylated lysine group to puromycin, a masked cytotoxic agent is created, which is serially activated by HDAC and an endogenous protease cathepsin L (CTSL) that remove the acetyl group first and then the unacetylated lysine group liberating puromycin. The agent selectively kills human cancer cell lines with high HDAC and CTSL activities. In vivo studies confirm tumour growth inhibition in prodrug-treated mice bearing human cancer xenografts. This cancer-selective cleavage of the masking group is a promising strategy for the next generation of anticancer drug development that could be applied to many other cytotoxic agents.

Qiao S, Tao S, Rojo de la Vega M, et al.
The antimalarial amodiaquine causes autophagic-lysosomal and proliferative blockade sensitizing human melanoma cells to starvation- and chemotherapy-induced cell death.
Autophagy. 2013; 9(12):2087-102 [PubMed] Free Access to Full Article Related Publications
Pharmacological inhibition of autophagic-lysosomal function has recently emerged as a promising strategy for chemotherapeutic intervention targeting cancer cells. Repurposing approved and abandoned non-oncological drugs is an alternative approach to the identification and development of anticancer therapeutics, and antimalarials that target autophagic-lysosomal functions have recently attracted considerable attention as candidates for oncological repurposing. Since cumulative research suggests that dependence on autophagy represents a specific vulnerability of malignant melanoma cells, we screened a focused compound library of antimalarials for antimelanoma activity. Here we report for the first time that amodiaquine (AQ), a clinical 4-aminoquinoline antimalarial with unexplored cancer-directed chemotherapeutic potential, causes autophagic-lysosomal and proliferative blockade in melanoma cells that surpasses that of its parent compound chloroquine. Monitoring an established set of protein markers (LAMP1, LC3-II, SQSTM1) and cell ultrastructural changes detected by electron microscopy, we observed that AQ treatment caused autophagic-lysosomal blockade in malignant A375 melanoma cells, a finding substantiated by detection of rapid inactivation of lysosomal cathepsins (CTSB, CTSL, CTSD). AQ-treatment was associated with early induction of energy crisis (ATP depletion) and sensitized melanoma cells to either starvation- or chemotherapeutic agent-induced cell death. AQ displayed potent antiproliferative effects, and gene expression array analysis revealed changes at the mRNA (CDKN1A, E2F1) and protein level (TP53, CDKN1A, CCND1, phospho-RB1 [Ser 780]/[Ser 807/811], E2F1) consistent with the observed proliferative blockade in S-phase. Taken together, our data suggest that the clinical antimalarial AQ is a promising candidate for repurposing efforts that aim at targeting autophagic-lysosomal function and proliferative control in malignant melanoma cells.

Primon M, Huszthy PC, Motaln H, et al.
Cathepsin L silencing enhances arsenic trioxide mediated in vitro cytotoxicity and apoptosis in glioblastoma U87MG spheroids.
Exp Cell Res. 2013; 319(17):2637-48 [PubMed] Related Publications
Despite improved treatment options, glioblastoma multiforme (GBM) remains the most aggressive brain tumour with the shortest post-diagnostic survival. Arsenite (As2O3) is already being used in the treatment of acute promyelocytic leukaemia (APL), yet its effects on GBM have not been evaluated in detail. In U87MG cell monolayers, we have previously shown that arsenite cytotoxicity significantly increases upon transient inhibition of lysosomal protease Cathepsin L (CatL). As multicellular spheroids more closely represent in vivo tumours, we aimed to evaluate the impact of permanent CatL silencing on arsenite treatment in U87MG spheroids. CatL was stably silenced using shRNA expression plasmid packed lentiviruses. By using metabolic- and cell viability assays, we demonstrated that long-term CatL silencing significantly increased arsenite cytotoxicity in U87MG spheroids. Silenced CatL also increased arsenite-mediated apoptosis in spheroids via elevated p53 expression, Bax/Bcl2 ratio and caspase 3/7 activity, though with lower efficacy than in monolayers. Arsenite cytotoxicity was enhanced by lower CatL activity, since similar cytotoxicity increase was also observed using the novel CatL inhibitor AT094. The results have significant translational impact, since stable CatL silencing would enable the application of lower systemic doses of arsenite to achieve the desired cytotoxic effects on GBMs in vivo.

Roberts I, O'Connor D, Roy A, et al.
The impact of trisomy 21 on foetal haematopoiesis.
Blood Cells Mol Dis. 2013; 51(4):277-81 [PubMed] Free Access to Full Article Related Publications
The high frequency of a unique neonatal preleukaemic syndrome, transient abnormal myelopoiesis (TAM), and subsequent acute myeloid leukaemia in early childhood in patients with trisomy 21 (Down syndrome) points to a specific role for trisomy 21 in transforming foetal haematopoietic cells. N-terminal truncating mutations in the key haematopoietic transcription factor GATA1 are acquired during foetal life in virtually every case. These mutations are not leukaemogenic in the absence of trisomy 21. In mouse models, deregulated expression of chromosome 21-encoded genes is implicated in leukaemic transformation, but does not recapitulate the effects of trisomy 21 in a human context. Recent work using primary human foetal liver and bone marrow cells, human embryonic stem cells and iPS cells shows that prior to acquisition of GATA1 mutations, trisomy 21 itself alters human foetal haematopoietic stem cell and progenitor cell biology causing multiple abnormalities in myelopoiesis and B-lymphopoiesis. The molecular basis by which trisomy 21 exerts these effects is likely to be extremely complex, to be tissue-specific and lineage-specific and to be dependent on ontogeny-related characteristics of the foetal microenvironment.

Ajeawung NF, Faure R, Jones C, Kamnasaran D
Preclinical evaluation of dipotassium bisperoxo (picolinato) oxovanadate V for the treatment of pediatric low-grade gliomas.
Future Oncol. 2013; 9(8):1215-29 [PubMed] Related Publications
AIM: The treatment of pediatric low-grade gliomas with current treatment modalities still remains ineffective among a subset of patients; hence, justifying the need to further investigate more effective therapies. Dipotassium bisperoxo (picolinato) oxovanadate V (Bpv[pic]), is a derivative of the trace metal vanadium and a potent inhibitor of protein tyrosine phosphatases, which are important mediators of oncogenic and tumor suppressive activities in cancers. In this study, we undertook a preclinical evaluation of the antineoplastic functions of Bpv(pic) in the treatment of pediatric low-grade gliomas.
MATERIALS & METHODS: We utilized pediatric low-grade glioma cell lines (Res186, Res259 and R286) in a wide variety of cancer assays to determine whether Bpv(pic) can abrogate the neoplastic properties of these cells.
RESULTS: Our preclinical evaluation of the antineoplastic properties of Bpv(pic) in pediatric low-grade gliomas reveals a significant dose-dependent decrease in cell viability as a consequence of decreased proliferation and sustained induction of growth arrest and apoptosis. Bpv(pic) significantly decreases cell migration/invasion and anchorage-independent growth in soft agarose. Within cells, Bpv(pic) functions by attenuating CDC25A activity, and by decreasing the expression of multiple protein tyrosine phosphatases, DNA repair genes, microtubule-associated genes, such as PLK1, AURKA and HDAC6, and conversely augmenting the expression of proapoptotic mediators such as BAK, AIFM and CTSL1.
CONCLUSION: Collectively, our data strongly suggest novel evidence of Bpv(pic) being a potent antineoplastic drug and a suitable alternative for the treatment of pediatric low-grade gliomas.

Grotsky DA, Gonzalez-Suarez I, Novell A, et al.
BRCA1 loss activates cathepsin L-mediated degradation of 53BP1 in breast cancer cells.
J Cell Biol. 2013; 200(2):187-202 [PubMed] Free Access to Full Article Related Publications
Loss of 53BP1 rescues BRCA1 deficiency and is associated with BRCA1-deficient and triple-negative breast cancers (TNBC) and with resistance to genotoxic drugs. The mechanisms responsible for decreased 53BP1 transcript and protein levels in tumors remain unknown. Here, we demonstrate that BRCA1 loss activates cathepsin L (CTSL)-mediated degradation of 53BP1. Activation of this pathway rescued homologous recombination repair and allowed BRCA1-deficient cells to bypass growth arrest. Importantly, depletion or inhibition of CTSL with vitamin D or specific inhibitors stabilized 53BP1 and increased genomic instability in response to radiation and poly(adenosine diphosphate-ribose) polymerase inhibitors, compromising proliferation. Analysis of human breast tumors identified nuclear CTSL as a positive biomarker for TNBC, which correlated inversely with 53BP1. Importantly, nuclear levels of CTSL, vitamin D receptor, and 53BP1 emerged as a novel triple biomarker signature for stratification of patients with BRCA1-mutated tumors and TNBC, with potential predictive value for drug response. We identify here a novel pathway with prospective relevance for diagnosis and customization of breast cancer therapy.

Ono M, Tanaka RJ, Kano M, Sugiman T
Visualising the cross-level relationships between pathological and physiological processes and gene expression: analyses of haematological diseases.
PLoS One. 2013; 8(1):e53544 [PubMed] Free Access to Full Article Related Publications
The understanding of pathological processes is based on the comparison between physiological and pathological conditions, and transcriptomic analysis has been extensively applied to various diseases for this purpose. However, the way in which the transcriptomic data of pathological cells relate to the transcriptomes of normal cellular counterparts has not been fully explored, and may provide new and unbiased insights into the mechanisms of these diseases. To achieve this, it is necessary to develop a method to simultaneously analyse components across different levels, namely genes, normal cells, and diseases. Here we propose a multidimensional method that visualises the cross-level relationships between these components at three different levels based on transcriptomic data of physiological and pathological processes, by adapting Canonical Correspondence Analysis, which was developed in ecology and sociology, to microarray data (CCA on Microarray data, CCAM). Using CCAM, we have analysed transcriptomes of haematological disorders and those of normal haematopoietic cell differentiation. First, by analysing leukaemia data, CCAM successfully visualised known relationships between leukaemia subtypes and cellular differentiation, and their characteristic genes, which confirmed the relevance of CCAM. Next, by analysing transcriptomes of myelodysplastic syndromes (MDS), we have shown that CCAM was effective in both generating and testing hypotheses. CCAM showed that among MDS patients, high-risk patients had transcriptomes that were more similar to those of both haematopoietic stem cells (HSC) and megakaryocyte-erythroid progenitors (MEP) than low-risk patients, and provided a prognostic model. Collectively, CCAM reveals hidden relationships between pathological and physiological processes and gene expression, providing meaningful clinical insights into haematological diseases, and these could not be revealed by other univariate and multivariate methods. Furthermore, CCAM was effective in identifying candidate genes that are correlated with cellular phenotypes of interest. We expect that CCAM will benefit a wide range of medical fields.

Ajeawung NF, Maltais R, Jones C, et al.
Viability screen on pediatric low grade glioma cell lines unveils a novel anti-cancer drug of the steroid biosynthesis inhibitor family.
Cancer Lett. 2013; 330(1):96-105 [PubMed] Related Publications
Pediatric low grade gliomas are the most common central nervous system tumors and are still incurable among a subset of patients despite current treatment modalities. Steroid biosynthesis occurs in a wide variety of organs including the brain, to mediate an assortment of functions, including a proposed role in the growth of gliomas. Hence, targeting steroid biosynthesis and/or their signaling pathways, is anticipated as an effective approach for treating gliomas. In this study, we investigated whether our chemical library of steroid inhibitors can modulate the growth of pediatric low grade glioma cell lines (Res186, Res259, R286), and subsequently identified a potent inhibitor of 17β-hydroxysteroid dehydrogenase type 3, referred to as DK16, which functions by attenuating cell viability, proliferation, migration/invasion and anchorage independent growth and conversely induces apoptosis and cell cycle arrest in a dose and duration dependent manner. Further investigations into the mechanisms of how DK16 functions showed that this drug increased the BAX/BCL2 expression ratio, induced phosphatidylserine externalization, and mitochondrial membrane depolarizations culminating to the release and nuclear translocation of AIF. In addition, treatments of low grade glioma cell lines with DK16 increased the expression of pro-apoptotic mediators including CDK2 and CTSL1, and with the converse diminished expression of pro-survival and migratory/invasion genes like PRKCA, TERT, MAPK8, MMP1 and MMP2. Our findings collectively demonstrate the potent anti-neoplastic properties of DK16, a steroid biosynthesis inhibitor, on the growth of pediatric low grade gliomas.

Yin M, Soikkeli J, Jahkola T, et al.
TGF-β signaling, activated stromal fibroblasts, and cysteine cathepsins B and L drive the invasive growth of human melanoma cells.
Am J Pathol. 2012; 181(6):2202-16 [PubMed] Related Publications
Accumulating evidence indicates that interactions between cancer cells and stromal cells are important for the development/progression of many cancers. Herein, we found that the invasive growth of melanoma cells in three-dimensional-Matrigel/collagen-I matrices is dramatically increased on their co-culture with embryonic or adult skin fibroblasts. Studies with fluorescent-labeled cells revealed that the melanoma cells first activate the fibroblasts, which then take the lead in invasion. To identify the physiologically relevant invasion-related proteases involved, we performed genome-wide microarray analyses of invasive human melanomas and benign nevi; we found up-regulation of cysteine cathepsins B and L, matrix metalloproteinase (MMP)-1 and -9, and urokinase- and tissue-type plasminogen activators. The mRNA levels of cathepsins B/L and plasminogen activators, but not MMPs, correlated with metastasis. The invasiveness/growth of the melanoma cells with fibroblasts was inhibited by cell membrane-permeable inhibitors of cathepsins B/L, but not by wide-spectrum inhibitors of MMPs. The IHC analysis of primary melanomas and benign nevi revealed cathepsin B to be predominantly expressed by melanoma cells and cathepsin L to be predominantly expressed by the tumor-associated fibroblasts surrounding the invading melanoma cells. Finally, cathepsin B regulated TGF-β production/signaling, which was required for the activation of fibroblasts and their promotion of the invasive growth of melanoma cells. These data provide a basis for testing inhibitors of TGF-β signaling and cathepsins B/L in the therapy of invasive/metastatic melanomas.

Zhou L, El-Deiry W, Wang W, et al.
Extracellular protease imaging for cell mass tracking of xenografted human malignant pleural mesothelioma.
Oncol Rep. 2012; 28(3):883-8 [PubMed] Related Publications
Malignant pleural mesothelioma (MPM) is locally aggressive and challenging to quantitate non-invasively in vivo, particularly in orthotopic models of disease. We describe imaging of extracellular protease activity, typically elevated in locally aggressive tumors, as a novel method for tracking MPM in vivo. Mice bearing human MPM subcutaneous flank xenografted tumors were imaged with ProSense 680, an optical imaging agent of extracellular cysteine protease activity. The relative contribution of extracellular cysteine proteases to the ProSense tumor signal was estimated using RT-PCR quantitation of cysteine protease RNA expression of the MPM cell lines and compared to ArrayExpress microarray RNA expression data from human MPM tumors. Feasibility of orthotopic intraperitoneal MPM cell mass tracking with fluorescence signal was evaluated using CellVue Maroon-coated MSTO-211H and compared to bioluminescent signal using luciferase-transfected MSTO-211H cells. ProSense 680 yielded a robust tumor signal in MPM subcutaneous grafts, primarily resulting from MPM secretion of cathepsin L demonstrated not only by RT-PCR data on MPM cell lines but also by microarray expression data from resected human patient tumors. CellVue Maroon intraperitoneal tumor signal was robust and durable indicating feasibility of intraperitoneal cell mass tracking of orthotopically-xenografted MPM. Optical imaging of extracellular cysteine protease activity is useful for tracking MPM tumor cell mass in vivo. Intraperitoneal MPM cell mass tracking of fluorescently labeled tumor is feasible.

Yu JB, Zhang YC, Yang QP, et al.
Invasion-associated genes identified by gene expression profiling in extranodal natural killer/T-cell lymphoma, nasal type.
Leuk Lymphoma. 2013; 54(1):90-8 [PubMed] Related Publications
To identify invasion-associated genes in extranodal natural killer (NK)/T-cell lymphoma, we performed microarray analysis on seven tumor samples and two control pools (composed of normal NK cells and T cells, tonsil and spleen) using Affymetrix GeneChip. Compared with all control pools, 59 uniquely expressed genes were discovered in the tumor samples. Overexpressed genes related to proteolysis, cell motility and chemotaxis, including CTSL, uPAR, TIMP-1, CXCL9, CXCL11 and DEFB1, were identified. Comparing the gene expression profiles of five upper aerodigestive tract (UAT) cases with two non-UAT cases, we found some overexpressed genes in non-UAT cases related to proteolysis and cell adhesion function, including matrix metalloproteinase 9 (MMP-9). Immunohistochemistry detection was performed on 34 paraffin sections to evaluate the expression of selected genes. A correlation of urokinase-type plasminogen activator receptor (uPAR) expression with MMP-9 expression was revealed. Analysis of prognosis demonstrated that expressions of MMP-2 and MMP-9 were closely correlated with a poor prognosis. These invasion-associated genes may become targets for diagnostic and therapeutic procedures.

Luistro LL, Rosinski JA, Bian H, et al.
Development and characterization of a preclinical ovarian carcinoma model to investigate the mechanism of acquired resistance to trastuzumab.
Int J Oncol. 2012; 41(2):639-51 [PubMed] Related Publications
Trastuzumab (Herceptin®) is a humanized monoclonal antibody designed to bind and inhibit the function of the human epidermal growth factor receptor 2 (HER2)/erbB2 receptor. Trastuzumab has demonstrated clinical activity in several types of HER2-overexpressing epithelial tumors, such as breast and metastatic gastric or gastroesophageal junction cancer. Relapse and therapeutic resistance, however, still occur in a subset of patients treated with regimens including trastuzumab, despite significant improvements in response rates, survival and quality of life. To investigate the potential mechanisms of acquired therapeutic resistance to trastuzumab, we developed a preclinical model of human ovarian cancer cells, SKOV-3 Herceptin-resistant (HR), and examined the corresponding changes in gene expression profiles. SKOV-3 HR cells were developed by in vivo serial passaging of parental trastuzumab-sensitive SKOV-3 cells. Following four rounds of serial transplantation of 'break-through' xenograft tumors under trastuzumab treatment, significant and reproducible differences in the effects of trastuzumab treatment between SKOV-3 HR and SKOV-3 cells in vivo and in vitro were revealed. SKOV-3 HR cells retained HER2 protein expression but were unaffected by the antiproliferative effects of trastuzumab. The trastuzumab binding affinity for SKOV-3 HR cells was diminished, despite these cells having more binding sites for trastuzumab. Microarray expression profiling (MEP) was performed to determine the genes involved in the resistance mechanism. Functional analysis revealed the differential expression of genes potentially involved in angiogenesis, metastasis, differentiation and proliferation, such as mucin1 (MUC1). Immunohistochemical staining of SKOV-3 HR cells demonstrated a marked overexpression of MUC1. Based on these data, we hypothesize that the overexpression of MUC1 may hinder trastuzumab binding to HER2 receptors, abrogating the antitumor effects of trastuzumab and thus could contribute to resistance to therapy. Moreover, the resultant MEP preclinical gene signature in this preclinical model system may provide the basis for further investigation of potential clinical mechanisms of resistance to trastuzumab.

Rafn B, Nielsen CF, Andersen SH, et al.
ErbB2-driven breast cancer cell invasion depends on a complex signaling network activating myeloid zinc finger-1-dependent cathepsin B expression.
Mol Cell. 2012; 45(6):764-76 [PubMed] Related Publications
Aberrant ErbB2 receptor tyrosine kinase activation in breast cancer is strongly linked to an invasive disease. The molecular basis of ErbB2-driven invasion is largely unknown. We show that cysteine cathepsins B and L are elevated in ErbB2 positive primary human breast cancer and function as effectors of ErbB2-induced invasion in vitro. We identify Cdc42-binding protein kinase beta, extracellular regulated kinase 2, p21-activated protein kinase 4, and protein kinase C alpha as essential mediators of ErbB2-induced cysteine cathepsin expression and breast cancer cell invasiveness. The identified signaling network activates the transcription of cathepsin B gene (CTSB) via myeloid zinc finger-1 transcription factor that binds to an ErbB2-responsive enhancer element in the first intron of CTSB. This work provides a model system for ErbB2-induced breast cancer cell invasiveness, reveals a signaling network that is crucial for invasion in vitro, and defines a specific role and targets for the identified serine-threonine kinases.

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