Expression Of Lumican Research Articles

ITRAQ-based quantitative proteomic analysis reveals potential early diagnostic markers of clear-cell Renal cell carcinoma.

Early detection is the key to improve the prognosis of kidney cancer. This study profiled and identified differentially expressed serum proteins in stage T1a renal cell carcinoma (RCC) using isobaric tags for relative and absolute quantification (iTRAQ)-based mass spectrometry. A total amount of 99 serum samples including 29 patients with ccRCC, 24 patients with a benign kidney mass, 28 patients with another type of urological tumor (20 cases of transitional cell carcinoma and 8 cases of prostate cancer or a male genital tumor), and 18 healthy controls were subjected to iTRAQ-based mass spectrometry. ProteinPilot software was used to identify the differentially expressed serum proteins in RCC compared to the other three populations. Hierarchical clustering analysis according to The Cancer Genome Atlas (TCGA) RCC database was then performed as the cross-platform validation. Immunohistochemistry was performed to verify the expression of selected proteins in tissue samples from these subjects. iTRAQ identified 27 differentially expressed serum proteins in the RCC patients, and 11 of these proteins were cross validated in RCC tissues from the TCGA database. The expression of C1QC, C1QB, S100A8, S100A9, ceruplasmin, and lumican was verified and associated with the tumor stage and/or grade. There were 27 differentially expressed proteins in early-stage RCC identified by iTRAQ; among them, the expression of C1QC, C1QB, S100A8, S100A9, ceruplasmin, and lumican were associated with the tumor stage and/or grade. Further studies are needed to confirm these data for their use as biomarkers for the early detection of RCC.

TNF-α–stimulated fibroblasts secrete lumican to promote fibrocyte differentiation

In healing wounds and fibrotic lesions, fibroblasts and monocyte-derived fibroblast-like cells called fibrocytes help to form scar tissue. Although fibrocytes promote collagen production by fibroblasts, little is known about signaling from fibroblasts to fibrocytes. In this report, we show that fibroblasts stimulated with the fibrocyte-secreted inflammatory signal tumor necrosis factor-α secrete the small leucine-rich proteoglycan lumican, and that lumican, but not the related proteoglycan decorin, promotes human fibrocyte differentiation. Lumican competes with the serum fibrocyte differentiation inhibitor serum amyloid P, but dominates over the fibroblast-secreted fibrocyte inhibitor Slit2. Lumican acts directly on monocytes, and unlike other factors that affect fibrocyte differentiation, lumican has no detectable effect on macrophage differentiation or polarization. α2β1, αMβ2, and αXβ2 integrins are needed for lumican-induced fibrocyte differentiation. In lung tissue from pulmonary fibrosis patients with relatively normal lung function, lumican is present at low levels throughout the tissue, whereas patients with advanced disease have pronounced lumican expression in the fibrotic lesions. These data may explain why fibrocytes are increased in fibrotic tissues, suggest that the levels of lumican in tissues may have a significant effect on the decision of monocytes to differentiate into fibrocytes, and indicate that modulating lumican signaling may be useful as a therapeutic for fibrosis.

Lumican is overexpressed in lung adenocarcinoma pleural effusions.

Adenocarcinoma (AdC) is the most common lung cancer subtype and is often associated with pleural effusion (PE). Its poor prognosis is attributable to diagnostic delay and lack of effective treatments and there is a pressing need in discovering new biomarkers for early diagnosis or targeted therapies. To date, little is known about lung AdC proteome. We investigated protein expression of lung AdC in PE using the isobaric Tags for Relative and Absolute Quantification (iTRAQ) approach to identify possible novel diagnostic/prognostic biomarkers. This provided the identification of 109 of lung AdC-related proteins. We further analyzed lumican, one of the overexpressed proteins, in 88 resected lung AdCs and in 23 malignant PE cell-blocks (13 lung AdCs and 10 non-lung cancers) using immunohistochemistry. In AdC surgical samples, lumican expression was low in cancer cells, whereas it was strong and diffuse in the stroma surrounding the tumor. However, lumican expression was not associated with tumor grade, stage, and vascular/pleural invasion. None of the lung cancer cell-blocks showed lumican immunoreaction, whereas those of all the other tumors were strongly positive. Finally, immunoblotting analysis showed lumican expression in both cell lysate and conditioned medium of a fibroblast culture but not in those of A549 lung cancer cell line. PE is a valid source of information for proteomic analysis without many of the restrictions of plasma. The high lumican levels characterizing AdC PEs are probably due to its release by the fibroblasts surrounding the tumor. Despite the role of lumican in lung AdC is still elusive, it could be of diagnostic value.

Effect of interleukin-1beta and dehydroepiandrosterone on the expression of lumican and fibromodulin in fibroblast-like synovial cells of the human temporomandibular joint.

Several epidemiological studies have reported that temporomandibular disorders (TMDs) are more prevalent in women than in men. It has recently been proposed that sex hormones such as estrogen, testosterone and dehydroepiandrosterone (DHEA) are involved with the pathogenesis of TMDs. Although studies have investigated the relationship between estrogen and testosterone and the restoration of TMDs, the relationship between DHEA and TMDs is unknown. The synovial tissue of the temporomandibular joint (TMJ) is made up of connective tissue with an extracellular matrix (ECM) composed of collagen and proteoglycan. One proteoglycan family, comprised of small leucine-rich repeat proteoglycans (SLRPs), was found to be involved in collagen fibril formation and interaction. In recent years, the participation of SLRPs such as lumican and fibromodulin in the internal derangement of TMJ has been suggested. Although these SLRPs may contribute to the restoration of the synovium, their effect is still unclear. The purpose of this study was to investigate the effect of DHEA, a sex hormone, on the expression of lumican and fibromodulin in human temporomandibular specimens and in cultured human TMJ fibroblast-like synovial cells in the presence or absence of the pro-inflammatory cytokine interleukin-1beta (IL-1beta). In the in vivo study, both normal and osteoarthritic (OA) human temporomandibular synovial tissues were immunohistochemically examined. In the in vitro study, five fibroblast-like synoviocyte (FLS) cell lines were established from human TMJ synovial tissue of patients with osteoarthritis. The subcultured cells were then incubated for 3, 6, 12 or 24 h with/without IL-1beta (1 ng/mL) in the presence or absence of DHEA (10 μM). The gene expression of lumican and fibromodulin was examined using the real-time polymerase chain reaction (PCR) and their protein expression was examined using immunofluorescent staining. We demonstrated that the expression of lumican differs from that of fibromodulin in synovial tissue and furthermore, that IL-1beta induced a significant increase in lumican mRNA and immunofluorescent staining in FLS compared to cells without IL-1beta. DHEA plus IL-1beta induced a significant increase in fibromodulin, but not in lumican mRNA, compared to DHEA alone, IL-1beta alone and in the absence of DHEA and IL-1beta. In immunofluorescent staining, weaker fibromodulin staining of FLS cells was observed in cells cultured in the absence of both DHEA and IL-1beta compared to fibromodulin staining of cells cultured with DHEA alone, with DHEA plus IL-1beta, or with IL-1beta alone. These results indicate that DHEA may have a protective effect on synovial tissue in TMJ by enhancing fibromodulin formation after IL-1beta induced inflammation. DHEA enhancement of fibromodulin expression may also exert a protective effect against the hyperplasia of fibrous tissue that TGF-beta1 induces. In addition lumican and fibromodulin are differentially expressed under different cell stimulation conditions and lumican and fibromodulin may promote regeneration of the TMJ after degeneration and deformation induced by IL-1beta.

Extracellular lumican inhibits pancreatic cancer cell growth and is associated with prolonged survival after surgery.

To evaluate the relevance between lumican expression patterns and the clinical course of patients with pancreatic ductal adenocarcinoma (PDAC), and to investigate the role of lumican in PDAC progression. One hundred thirty-one patient tumors were chosen for tissue microarray staining, and Cox regression analysis was used to test the associations between lumican expression and clinical, pathologic, and oncologic outcomes in all patients. Primary PDAC cells and recombinant human lumican protein were used to establish a working model to mimic the in vivo interactions between stromal lumican and PDAC cells. Using this model, we tested the effects of lumican on EGFR signaling via Akt and hypoxia-inducible factor-1α (HIF1α) and its subsequent influence on glucose consumption, lactate production, intracellular ATP, and apoptotic cell death. Lumican was present in the stroma surrounding PDAC cells in roughly one-half of primary tumors and the direct xenografts. Patients with stromal lumican were associated with a profound reduction in metastatic recurrence after surgery and 3-fold longer survival than patients without stromal lumican. In PDAC cells, extracellular lumican reduced EGFR expression and phosphorylation through enhanced dimerization and internalization of EGFR and the resultant inhibition of Akt kinase activity. Lumican also reduced HIF1α expression and activity via Akt. PDAC cells with enhanced HIF1α activity were resistant to lumican-induced inhibition of glucose consumption, lactate production, intracellular ATP, and apoptosis. There is a positive association between stromal lumican in primary PDAC tumors and prolonged survival after tumor resection. Lumican plays a restrictive role in EGFR-expressing pancreatic cancer progression.

Gene expression profiling of giant cell tumor of bone reveals downregulation of extracellular matrix components decorin and lumican associated with lung metastasis.

Giant cell tumor of bone (GCTB) displays worrisome clinical features such as local recurrence and occasionally metastatic disease which are unpredictable by morphology. Additional routinely usable biomarkers do not exist. Gene expression profiles of six clinically defined groups of GCTB and one group of aneurysmal bone cyst (ABC) were determined by microarray (n = 33). The most promising differentially expressed genes were validated by Q-PCR as potential biomarkers in a larger patient group (n = 41). Corresponding protein expression was confirmed by immunohistochemistry. Unsupervised hierarchical clustering reveals a metastatic GCTB cluster, a heterogeneous, non-metastatic GCTB cluster, and a primary ABC cluster. Balanced score testing indicates that lumican (LUM) and decorin (DCN) are the most promising biomarkers as they have lower level of expression in the metastatic group. Expression of dermatopontin (DPT) was significantly lower in recurrent tumors. Validation of the results was performed by paired and unpaired t test in primary GCTB and corresponding metastases, which proved that the differential expression of LUM and DCN is tumor specific rather than location specific. Our findings show that several genes related to extracellular matrix integrity (LUM, DCN, and DPT) are differentially expressed and may serve as biomarkers for metastatic and recurrent GCTB.

Abstract 4729: Expression of lumican is negatively associated with the risk of biochemical recurrence in human prostate cancer

Abstract We used DNA chip technology in a genetically engineered mouse model of prostate cancer, and identified lumican as a candidate biomarker in prostate cancer progression. Lumican is a small leucine-rich extracellular matrix protein that has been shown to modulate cell migration and proliferation during embryonic development, and tissue repair. Expression and distinct glycosylation patterns of lumican in several tumor and stromal tissues has been shown to play important roles in vascular invasion, differentiation, proliferation, and invasion. Our goal was to determine the clinical value of lumican as a biomarker for human prostate cancer. In order to do so, we examined gene expression in publicly available databases and confirmed the protein expression in tissue microarrays constructed from prostatectomy cases. Protein expression was examined by immunohistochemistry and expression scores were compared with clinicopathological features and disease progression. Our analysis shows that in human prostate cancer, stromal expression of lumican correlated inversely with clinicopathological features associated with disease progression. In addition, biochemical recurrence was significantly longer for patients with high expression of stromal lumican. Our findings suggest that lumican may be a strong candidate prognostic biomarker and warrants prospective validation. Citation Format: Marco A. De Velasco, Yuji Hatanaka, Takashi Oki, Yurie Kura, Yutaka Yamamoto, Kazuhiro Yoshimura, Nobutaka Shimizu, Masahiro Nozawa, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura. Expression of lumican is negatively associated with the risk of biochemical recurrence in human prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4729. doi:10.1158/1538-7445.AM2014-4729

Expression of Lumican in Hidroacanthoma Simplex and Clonal-Type Seborrheic Keratosis as a Potent Differential Diagnostic Marker

Lumican, a member of the small leucine-rich proteoglycan family, regulates the assembly and diameter of collagen fibers in the extracellular matrix of various tissues. The lumican expression correlates with pathological conditions and the growth and metastasis of various malignancies. In cutaneous neoplasms, the lumican expression is lower in advanced-stage malignant melanomas that invade the dermis than in early-stage melanomas. Furthermore, we have recently reported that the expression pattern of lumican is different from that of actinic keratosis and the Bowen disease. Lumican is positive in the poroid cells of intraepidermal sweat ducts; therefore, we examined the expression patterns of lumican in acanthotic-type seborrheic keratosis and Pinkus-type poroma followed by clonal-type seborrheic keratosis and hidroacanthoma simplex. The neoplastic cells of acanthotic-type seborrheic keratosis exhibited positive immunostaining in only 1 of 31 cases (3.23%), whereas the poroid cells of Pinkus-type poroma exhibited positive immunoreactivity in 26 of 28 patients (92.8%). In the hidroacanthoma simplex cases, lumican was expressed in poroid cells forming intraepidermal nests in 22 of 28 patients (78.6%), whereas the neoplastic cells in most cases of clonal-type seborrheic keratosis were negative for lumican. In some seborrheic keratosis cases that were positive for lumican in neoplastic cells, lumican was observed in squamoid cells but not in basaloid cells. Therefore, it is necessary to evaluate the immunoreactivity of lumican in seborrheic keratosis and in basaloid cells. These findings suggest that lumican is a potent differential diagnostic marker that distinguishes hidroacanthoma simplex from clonal-type seborrheic keratosis.

153 Novel Insights into the Pathophysiology of Hypertrophic Cardiomyopathy Using Label free Quantitative Proteomics

IntroductionThe genetic background of hypertrophic cardiomyopathy (HCM) is well described; however it fails to explain the phenotypic diversity characteristic of the disease. By performing an unbiased label-free quantitative proteomics analysis...

Lumican as a Novel Marker for Differential Diagnosis of Bowen Disease and Actinic Keratosis

Lumican, a member of the small leucine-rich proteoglycan family, regulates the assembly and diameter of collagen fibers in the extracellular matrix of various tissues. Lumican expression correlates with pathological conditions, including skin fragility, corneal opacification, and corneal and cardiac wound healing. Lumican is overexpressed in tumor cells, including in the breast, colorectal, neuroendocrine cell, uterine cervical, and pancreatic cancers. Lumican expression also correlates with the growth and metastasis of various malignancies. For example, lumican expression is lower in the dermis of malignant melanoma cases than in early-stage melanomas. However, the expression patterns and roles of lumican in nonmelanoma skin cancer have not been elucidated. In this study, we used immunohistochemistry and in situ hybridization to examine the expression patterns of lumican in normal skin, Bowen disease, and actinic keratosis. In normal skin, lumican was expressed in the collagen fibers in the dermis, acrosyringium, follicular epithelium, and sebocytes but not in epidermal keratinocytes. In Bowen disease, lumican was expressed in 34 (91.8%) of 37 patients. Notably, all cases of actinic keratosis were negative for lumican. These findings suggest that lumican plays an important role in the pathogenesis of Bowen disease and actinic keratosis and might be useful as an adjunct to the diagnosis for subtypes of 2 diseases: bowenoid actinic keratosis and Bowen disease in sun-exposed areas.

Small leucine-rich proteoglycans in the vertebrae of Atlantic salmon Salmo salar

We analysed the distribution and expression of the small leucine-rich proteoglycans (SLRPs) decorin, biglycan and lumican in vertebral columns of Atlantic salmon Salmo salar L. with and without radiographically detectable deformities. Vertebral deformities are a reoccurring problem in salmon and other intensively farmed species, and an understanding of the components involved in the pathologic development of the vertebrae is important in order to find adequate solutions to this problem. Using immunohistology and light microscopy, we found that in non-deformed vertebrae biglycan, lumican and decorin were all expressed in osteoblasts at the vertebral growth zones and at the ossification front of the chondrocytic arches. Hence, the SLRPs are expressed in regions where intramembranous and endochondral ossification take place. In addition, mRNA expression of biglycan, decorin and lumican was demonstrated in a primary osteoblast culture established from Atlantic salmon, supporting the in vivo findings. Transcription of the SLRPs increased during differentiation of the osteoblasts in vitro and where lumican mRNA expression increased later in the differentiation compared with decorin and biglycan. Intriguingly, in vertebral fusions, biglycan, decorin and lumican protein expression was extended to trans-differentiating cells at the border between arch centra and osteoblast growth zones. In addition, mRNA expression of biglycan, decorin and lumican differed between non-deformed and fused vertebrae, as shown by quantitative PCR (qPCR). Western blotting revealed an additional band of biglycan in fused vertebrae which had a higher molecular weight than in non-deformed vertebrae. Fourier-transform infrared (FTIR) spectroscopy revealed more spectral focality in the endplates of vertebral fusions and significantly more non-reducible collagen crosslinks compared with non-deformed vertebrae, thus identifying differences in bone structure.

Diphlorethohydroxycarmalol of Ishige okamurae and Caffeine Modified the Expression of Extracellular Fibrillars during Adipogenesis of Mouse Subcutaneous Adipose Derived Stem Cell.

Although, one of the etiologies of localized lipodystrophy of the subcutaneous connective tissue (cellulite) is the histological alternation of adipose tissue, the characteristics of expression of the components of extracellular matrix (ECM) components during adipogenesis are not uncovered. In this study, the effects of caffeine and Ishige okamurae originated diphlorethohydroxycarmalol (DPHC) on the expression of extracellualr fibers was analyzed with quantitative RT-PCR during differentiation induction of mouse subcutaneous adipose derived stem cells (msADSC) into adipocyte. The expression levels of Col1a, Col3a1, and Col61a were decreased by the adipogenci induction in a time-dependent manners. However, Col2a mRNA and Col4a1 mRNA expressions were oposit to them. Caffeine and DPHC stimulated the changes of the expression of these collagens. Eln mRNA expression was increased by induction. DPHC stimulated the expression of it. Mfap5 mRNA expression was deceased in both adipogenic cell and matured adipocytes. Caffeine suppressed the expression of Mfap5 but the effect of DPHC was different by the concentration. The expression of bioglycan, decorin, and lumican were also modified by caffeine and DPHC in a concentration-dependent manner. Based on this study, we revealed firstly the effects of caffeine and DPHC on the expression of collagens, elastin, and glycoproteins during adipogenesis of msADSCs. Those results suggest that DPHC may have antiadipogenic effect and has more positive effets on normal adipose tissue generation and work as suppressor the abnormality of ECM structure. Such results indicate that DPHC can be applied in keeping the stability of the ECM of adipogenic tissues.

Expression of Lumican in Invasive and Metastatic Endometrial Carcinoma Tissues

Objective To explore the expression profiles of Lumican in invasive and metastatic endometrial carcinoma.Methods Forty-eight cases of endometrial carcinoma and paired normal endometrium tissues were applied for detecting the expression of Lumican.The mRNA and protein expression profiles of Lumican were analysed by RT-PCR and Western blot,respectively.SPSS13.0 statistical software was adopted to analyze the expression difference of Lumican in endometrial carcinoma.Results Compared with the normal endometrium tissues,mRNA and protein expression of Lumican were down-regulated in endometrial carcinoma tissues [(0.54±0.042)vs.(0.87±0.035);(0.42±0.026) vs.(0.83±0.037)],respectively(P0.05).It was showed evidently difference of Lumican expression in 48 cases of endometrial carcinoma,including superficial invasive group(22 cases),deep invasive group(11 cases) /cervix invasive group(11 cases) and lymph metastatic group(4 cases).Conclusion Lumican was downregulated in endometrial carcinoma,Lumican expression was negatively related to the invasion and metastasis of endometrial carcinoma.Low expression of Lumican may be involved in the malignant biological behavior of invasion and metastasis in the endometrial carcinoma.

Analysis of protein expression regulated by lumican in PANC-1 cells using shotgun proteomics

Lumican, a member of the class II small leucine-rich proteoglycan family, regulates the assembly and diameter of collagen fibers in the extracellular matrix of various tissues. We previously reported that lumican expression in the stromal tissues of pancreatic ductal adenocarcinoma (PDAC) correlates with tumor invasion, and tends to correlate with poor prognosis. Lumican stimulates growth and inhibits the invasion of a PDAC cell line. In the present study, we performed a global shotgun proteomic analysis using lumican-overexpressing PANC‑1 cells and lumican downregulated PANC‑1 cells to identify candidate proteins that are regulated by lumican and related to cell growth and invasion in PDAC cells. A total of 448 proteins were identified from lumican-overexpressing PANC‑1 and control cells. Additionally, 451 proteins were identified from lumican-downregulated PANC‑1 cells and control cells. As a result of semi-quantification based on spectral counting, 174 differentially expressed proteins were identified by lumican upregulation, and 143 differentially expressed proteins were identified by lumican downregulation. The expression levels of 24 proteins, including apoptosis- and invasion-related proteins correlated with lumican expression levels. It is likely that the expression of these proteins is regulated by lumican, and that they are involved in apoptosis and invasion in PDAC. These findings suggest that lumican may be involved in cell growth and invasion through the regulation of these 24 proteins expressed in PDAC.

Lumican Exhibits Anti-Angiogenic Activity in a Context Specific Manner

A series of overexpression studies have shown that lumican suppresses angiogenesis in tumors produced from pancreatic adenocarcinoma, fibrosarcoma, and melanoma tumor cells. Despite lumican's anti-angiogenic activity, a clear correlation of differential expression of lumican in various cancers and cancer malignancy has failed to emerge. Therefore, we hypothesized that either 1.) endogenously expressed lumican is not anti-angiogenic or alternatively that 2.) lumican exhibits angiostatic activity only in limited microenvironments. Previously, lumican was shown to suppress tumor growth and angiogenesis in subcutaneously injected PanO2 pancreatic adenocarcinoma cells. Therefore, to determine if endogenously expressed lumican is anti-angiogenic we subcutaneously injected PanO2 cells into wild-type and lumican knockout mice and compared tumor growth and vascular densities of the resulting tumors. We found that tumors grown in lumican knockout animals were larger and contained significantly elevated vascular densities compared to those grown in wild-type mice. Interestingly however lumican knockout animals did not exhibit enhanced angiogenesis in aortic ring assays, matrigel plugs, or healing wound biopsies raising the possibility that lumican suppresses angiogenesis only in tumor microenvironments. To test this possibility, we sought a tumor model wherein lumican did not exhibit anti-angiogenic activity. Utilizing the 4T1 breast cancer model, we found that lumican suppressed 4T1 tumor growth and lung metastasis, but not angiogenesis. In conclusion, these results show that the angiostatic activity of lumican is dependent on currently undefined microenvironmental cues and therefore helps to understand why differential expression of lumican does not consistently correlate with human tumor malignancy.

Proteoglycan Expression in Normal Human Prostate Tissue and Prostate Cancer

Proteoglycans (PGs) are expressed on the cell surface and extracellular matrix of all mammalian cells and tissues, playing an important role in cell-cell and cell-matrix interactions and signaling. Changes in the expression and functional properties of individual PGs in prostate cancer are shown, although common patterns of PGs expression in normal and tumour prostate tissues remain unknown. In this study, expression of cell surface and stromal proteoglycans (glypican-1, perlecan, syndecan-1, aggrecan, versican, NG2, brevican, decorin, and lumican) in normal tissue and prostate tumours was determined by RT-PCR analysis and immunostaining with core protein- and GAG-specific antibodies. In normal human prostate tissue, versican, decorin, and biglycan were predominant proteoglycans localised in tissue stroma, and syndecan-1 and glypican-1 were expressed mainly by epithelial cells. In prostate tumours, complex changes in proteoglycans occur, with a common trend towards decrease of decorin and lumican expression, overall increase of syndecan-1 and glypican-1 expression in tumour stroma along with its disappearance in tumour epithelial cells, and aggrecan and NG2 expressions in some prostate tumours. All the changes result in the highly individual proteoglycan expression patterns in different prostate tumours, which may be potentially useful as molecular markers for prostate cancer personalised diagnosis and treatment.

Abstract 8: A role for lumican as a biomarker of disease progression in human prostate adenocarcinoma.

Abstract We previously identified altered lumican expression in prostate tumors from genetically modified mice. Lumican is a small leucine-rich extracellular matrix protein that has been shown to modulate cell migration and proliferation during embryonic development, and tissue repair. Expression and distinct glycosylation patterns of lumican in several tumor and stromal tissues has been shown to play important roles in vascular invasion, differentiation, proliferation, and invasion. To determine a possible role for lumican as a prognostic biomarker for prostate cancer, we examined protein expression in normal and tumor specimens from prostatectomy cases. Tissue microarrays were constructed and immunostained for lumican. Slides were digitized and the expression levels of lumican were scored in both the stroma and epithelia. Expression scores were compared with clinicopathological features and disease progression, defined as death or biochemical recurrence. Stromal Lumican expression in tumor was negatively associated with Gleason score, differentiation, node/metastasis status and disease progression. Progression free survival was significantly longer for patients with high expression of stromal lumican (HR=0.25; P=0.005). Based on this set, stromal expression of lumican correlated to good clinical outcome for patients with prostate cancer and thus appears to be a strong prognostic biomarker for disease progression. Citation Format: Marco A. De Velasco, Yuji Hatanaka, Yurie Kura, Naomi Ando, Emiko Fukushima, Yutaka Yamamoto, Nobutaka Shimizu, Masahiro Nozawa, Kazuhiro Yoshimura, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura. A role for lumican as a biomarker of disease progression in human prostate adenocarcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 8. doi:10.1158/1538-7445.AM2013-8

LMX1B‐Regulated Nephrogenesis: A Role for Proteoglycans

Lmx1b is a transcription factor necessary for kidney development. In humans, haploinsufficiency causes Nail Patella Syndrome frequently with chronic renal failure. In Lmx1b knockout mice, glomerular basement membrane formation is impaired, blocking filtration, urine production and long term survival. The mechanisms used by Lmx1b to direct basement membrane formation remain unclear. Recent microarray studies in the limb have implicated the proteoglycans Keratocan, Lumican, and Decorin (KLD) as downstream targets of Lmx1b. We hypothesized that Lmx1b might also regulate the KLD proteoglycans during kidney development.To determine the role of Lmx1b in regulating the KLD proteoglycans, we compared the expression patterns of Lmx1b, Podocin, Keratocan, Lumican, and Decorin in the developing chicken kidney using whole mount in situ hybridization.We found that Keratocan expression localized to nephric tubules and collecting ducts, Lumican expression was associated with nephric tubules, and Decorin expression surrounded Bowman's capsules and nephric tubules. Correspondingly, Lmx1b is expressed in Bowman's capsule and in nephric tubules. Thus, the expression of Decorin complements the expression of Lmx1b.Our data suggests Decorin is a target of Lmx1b regulation during nephrogenesis. Further research is needed to determine the functional role of KLD proteoglycans in kidney development.Grant Funding Source: Departmental

Lumican effects in the control of tumour progression and their links with metalloproteinases and integrins

Lumican is a member of the small leucine-rich proteoglycan family. It is present in numerous extracellular matrices of different tissues, such as muscle, cartilage, and cornea. In skin, lumican is present as a glycoprotein. It plays a critical role in collagen fibrillogenesis, as shown by knocking out of its gene in mice. A direct link between lumican expression and melanoma progression and metastasis has been demonstrated. Lumican was shown to impede tumour cell migration and invasion by directly interacting with the α2β1 integrin. In addition, an active sequence of the lumican core protein, called lumcorin, was identified as being responsible for inhibition of melanoma cell migration. Lumican was also shown to exert angiostatic properties by downregulating the proteolytic activity associated with endothelial cell membranes, particularly matrix metalloproteinase (MMP)-14 and MMP-9. Globally, lumican appears to be a potent agent for inhibiting tumour progression rather than tumorigenesis. However, progressive changes in proteoglycans occur in the tumour environment. The complexity and diversity of proteoglycan structure might be responsible for a variety of functions that regulate cell behaviour. Through their core protein and their glycosaminoglycan chains, proteoglycans can interact with growth factors and chemokines. These interactions affect cell signalling, motility, adhesion, growth, and apoptosis. This review summarizes recent data concerning lumican control of tumour progression in different cancers, with a particular focus on its interactions with MMPs and integrins. Its potential therapeutic implications are discussed.

Lumican expression in pancreatic ductal adenocarcinoma.

The present study was aimed to investigate lumican expression in and correlation with severity of pancreatic ductal adenocarcinoma (PDA). We assessed mRNA expression and protein localization (using immunohistochemistry) in PDA samples collected from 260 patients. Additionally, we compared lumican expression with expression of Ki-67, VEGF and mutated p53 proteins, which are markers of cancer progression. Expression levels of lumican mRNA and protein in cancer tissue were significantly higher than those in tumor-adjacent tissue (t=5.69, p<0.05). The stromal expression of lumican in poorly differentiated cases was significantly higher at stage T4 than stage T2-3 (χ²=21.06, p<0.05); similarly, the stromal expression of lumican was significantly higher in TNM stage III-IV than in stage I-Il (χ²=17.01, p<0.05). Additionally, expression of Ki67 was higher in poorly differentiated cases than in highly-moderately differentiated cases (χ²=13.06, p<0.05). Finally, in highly-moderately differentiated samples, stromal expression of lumican was negatively correlated with expression of Ki-67, VEGF and mutated P53 (p<0.05). Lumican expression is higher in pancreatic ductal adenocarcinoma than in tumor-adjacent tissue, and the correlation of lumican expression with TNM stage in poorly differentiated samples, in contrast with its negative correlation with expression of Ki-67, VEGF and mutated P53 mutation in highly-moderately differentiated samples.