Gene Summary

Gene:LYVE1; lymphatic vessel endothelial hyaluronan receptor 1
Aliases: HAR, XLKD1, LYVE-1, CRSBP-1
Summary:This gene encodes a type I integral membrane glycoprotein. The encoded protein acts as a receptor and binds to both soluble and immobilized hyaluronan. This protein may function in lymphatic hyaluronan transport and have a role in tumor metastasis. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, GeneCard, Gene
Protein:lymphatic vessel endothelial hyaluronic acid receptor 1
Source:NCBIAccessed: 27 February, 2015


What does this gene/protein do?
Show (16)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 27 February 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.

  • Cell Line
  • Hepatocellular Carcinoma
  • Sensitivity and Specificity
  • Membrane Glycoproteins
  • Lymphatic Vessels
  • Lymphatic Metastasis
  • Gene Expression Profiling
  • Messenger RNA
  • Liver Cirrhosis
  • LYVE1
  • Neoplasm Proteins
  • Staging
  • Chromosome 11
  • Vocal Cords
  • Vascular Endothelial Growth Factor D
  • siRNA
  • rho GTP-Binding Proteins
  • Polymerase Chain Reaction
  • Cancer Gene Expression Regulation
  • Disease Progression
  • Pancreatic Cancer
  • Lymphangiogenesis
  • Lymphatic System
  • Tumor Markers
  • Breast Cancer
  • Vascular Endothelial Growth Factor C
  • Angiogenesis Inducing Agents
  • Tumor Suppressor Proteins
  • Lymph Nodes
  • Gene Expression
  • Squamous Cell Carcinoma
  • Homeodomain Proteins
  • Immunohistochemistry
  • Liver Cancer
  • Neoplasm Metastasis
  • Vesicular Transport Proteins
  • Vascular Endothelial Growth Factors
  • Vascular Endothelial Growth Factor Receptor-3
  • Angiogenesis
  • Glycoproteins
Tag cloud generated 27 February, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

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: LYVE1 (cancer-related)

Gupta R, Kitaichi M, Inoue Y, et al.
Lymphatic manifestations of lymphangioleiomyomatosis.
Lymphology. 2014; 47(3):106-17 [PubMed] Related Publications
Lymphangioleiomyomatosis (LAM) is a slowly progressive, low grade, metastasizing neoplasm, associated with cellular invasion and cystic destruction of the pulmonary parenchyma. Although the source of LAM cells that infiltrate the lung is unknown, available evidence indicates that the disease spreads primarily through lymphatic channels, often involving abdominal, axial, and retroperitoneal nodes, suggestive of an origin in the pelvis. LAM cells harbor mutations in tuberous sclerosis genes and produce lymphangiogenic growth factors, which facilitate access to and movement through the lymphatic system and likely play an important role in destructive tissue remodeling in the lung. Lymphatic manifestations of LAM include thoracic duct wall invasion, lymphangioleiomyoma formation, chylous fluid collections in the peritoneal, pleural, and pericardial spaces, chyloptysis, chylocolporrheal chylometrorrhea, chyle leak from the umbilicus, chylous pulmonary congestion, and lower extremity lymphedema. LAM lesions express lymphangiogenic growth factors VEGF-C and VEGF-D; growth factor receptors, VEGFR-2 and VEGFR-3; and markers LYVE-1 and podoplanin, and are laced with chaotic lymphatic channels. Serum VEGF-D is elevated in 70% of patients with LAM and is a clinically useful diagnostic and prognostic biomarker. Molecular targeted therapy with sirolimus stabilizes lung function, is anti-lymphangiogenic, and is highly effective for the lymphatic and chylous complications of LAM. Future trials in patients with LAM who have lymphatic manifestations or elevated serum VEGF-D will likely focus on the VEGF-C/VEGF-D/VEGFR-3 axis.

Trabert B, Ness RB, Lo-Ciganic WH, et al.
Aspirin, nonaspirin nonsteroidal anti-inflammatory drug, and acetaminophen use and risk of invasive epithelial ovarian cancer: a pooled analysis in the Ovarian Cancer Association Consortium.
J Natl Cancer Inst. 2014; 106(2):djt431 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Regular aspirin use is associated with reduced risk of several malignancies. Epidemiologic studies analyzing aspirin, nonaspirin nonsteroidal anti-inflammatory drug (NSAID), and acetaminophen use and ovarian cancer risk have been inconclusive.
METHODS: We analyzed pooled data from 12 population-based case-control studies of ovarian cancer, including 7776 case patients and 11843 control subjects accrued between 1992 and 2007. Odds ratios (ORs) for associations of medication use with invasive epithelial ovarian cancer were estimated in individual studies using logistic regression and combined using random effects meta-analysis. Associations between frequency, dose, and duration of analgesic use and risk of ovarian cancer were also assessed. All statistical tests were two-sided.
RESULTS: Aspirin use was associated with a reduced risk of ovarian cancer (OR = 0.91; 95% confidence interval [CI] = 0.84 to 0.99). Results were similar but not statistically significant for nonaspirin NSAIDs, and there was no association with acetaminophen. In seven studies with frequency data, the reduced risk was strongest among daily aspirin users (OR = 0.80; 95% CI = 0.67 to 0.96). In three studies with dose information, the reduced risk was strongest among users of low dose (<100 mg) aspirin (OR = 0.66; 95% CI = 0.53 to 0.83), whereas for nonaspirin NSAIDs, the reduced risk was strongest for high dose (≥500 mg) usage (OR = 0.76; 95% CI = 0.64 to 0.91).
CONCLUSIONS: Aspirin use was associated with a reduced risk of ovarian cancer, especially among daily users of low-dose aspirin. These findings suggest that the same aspirin regimen proven to protect against cardiovascular events and several cancers could reduce the risk of ovarian cancer 20% to 34% depending on frequency and dose of use.

Su CH, Tzeng TY, Cheng C, Hsu MT
An H2A histone isotype regulates estrogen receptor target genes by mediating enhancer-promoter-3'-UTR interactions in breast cancer cells.
Nucleic Acids Res. 2014; 42(5):3073-88 [PubMed] Free Access to Full Article Related Publications
A replication-dependent histone H2A isotype, H2ac, is upregulated in MCF-7 cells and in estrogen receptor-positive clinical breast cancer tissues. Cellular depletion of this H2A isotype leads to defective estrogen signaling, loss of cell proliferation and cell cycle arrest at G0/G1 phase. H2ac mediates regulation of estrogen receptor target genes, particularly BCL2 and c-MYC, by recruiting estrogen receptor alpha through its HAR domain and facilitating the formation of a chromatin loop between the promoter, enhancer and 3'-untranslated region of the respective genes. These findings reveal a new role for histone isotypes in the regulation of gene expression in cancer cells, and suggest that these molecules may be targeted for anti-cancer drug discovery.

Ek WE, Levine DM, D'Amato M, et al.
Germline genetic contributions to risk for esophageal adenocarcinoma, Barrett's esophagus, and gastroesophageal reflux.
J Natl Cancer Inst. 2013; 105(22):1711-8 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Esophageal adenocarcinoma (EA) is an increasingly common cancer with poor survival. Barrett's esophagus (BE) is the main precursor to EA, and every year 0.12% to 0.5% of BE patients progress to EA. BE typically arises on a background of chronic gastroesophageal reflux (GERD), one of the risk factors for EA.
METHODS: We used genome-wide association data to investigate the genetic architecture underlying GERD, BE, and EA. We applied a method to estimate the variance explained (array heritability, h(2)g) and the genetic correlation (rg) between GERD, BE, and EA by considering all single nucleotide polymorphisms (SNPs) simultaneously. We also estimated the polygenic overlap between GERD, BE, and EA using a prediction approach. All tests were two-sided, except in the case of variance-explained estimation where one-sided tests were used.
RESULTS: We estimated a statistically significant genetic variance explained for BE (h(2)g = 35%; standard error [SE] = 6%; one-sided P = 1 × 10(-9)) and for EA (h(2)g = 25 %; SE = 5%; one-sided P = 2 × 10(-7)). The genetic correlation between BE and EA was found to be high (rg = 1.0; SE = 0.37). We also estimated a statistically significant polygenic overlap between BE and EA (one-sided P = 1 × 10(-6)), which suggests, together with the high genetic correlation, that shared genes underlie the development of BE and EA. Conversely, no statistically significant results were obtained for GERD.
CONCLUSIONS: We have demonstrated that risk to BE and EA is influenced by many germline genetic variants of small effect and that shared polygenic effects contribute to risk of these two diseases.

Langenes V, Svensson H, Börjesson L, et al.
Expression of the chemokine decoy receptor D6 is decreased in colon adenocarcinomas.
Cancer Immunol Immunother. 2013; 62(11):1687-95 [PubMed] Related Publications
Recruitment of immune cells to tumors is a complex process crucial for both inflammation-driven tumor progression and specific anti-tumor cytotoxicity. Chemokines control the directed migration of immune cells, and their actions are partly controlled by nonsignaling chemokine decoy receptors. The role of the receptors such as D6, Duffy antigen receptor for chemokines and ChemoCentryx chemokine receptor in immunity to tumors is still unclear. Using real-time PCR, we detected significantly decreased expression of D6 mRNA in colon tumors compared to unaffected mucosa. D6 protein was expressed by lymphatic endothelium and mononuclear cells in the colon lamina propria and detected by immunohistochemistry in two out of six tissue samples containing high D6 mRNA levels, whereas no staining was observed in any tissue samples expressing low mRNA levels. When examining the density of lymphatic vessels in colon tumors, we detected a marked increase in vessels identified by the lymphatic endothelial marker Lyve-1, excluding passive regulation of D6 due to decreased lymphatic vessel density. In parallel, the Treg-recruiting chemokine CCL22, which is sequestered by D6, was threefold increased in tumor tissue. Furthermore, we could show that low D6 expression correlated to more invasive tumors and that tumor location influences D6 expression, which is lower in the more distal parts of the colon. The data support that regulation of D6 by colon tumors results in altered levels of proinflammatory CC chemokines, thereby shaping the local chemokine network to favor tumor survival. This may have implications for the design of future immunotherapy for colon cancer.

Géraud C, Mogler C, Runge A, et al.
Endothelial transdifferentiation in hepatocellular carcinoma: loss of Stabilin-2 expression in peri-tumourous liver correlates with increased survival.
Liver Int. 2013; 33(9):1428-40 [PubMed] Related Publications
BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is a malignant tumour that is characterized by extensive vascular remodelling and responsiveness to treatment with the anti-angiogenic multikinase inhibitor sorafenib. The aim was to study endothelial remodelling in HCC.
METHODS: The murine inducible albumin-SV40-large T-antigen model and two tissue microarrays (TMA) with 295 tumourous and 83 peri-tumourous samples of 296 patients with HCC were analysed for expression of liver sinusoidal endothelial cell (LSEC)-specific marker proteins, stabilin-1 and stabilin-2, LYVE-1 and CD32b.
RESULTS: LSEC marker proteins were sequentially lost during HCC progression in the murine HCC model being absent from tumour nodules larger than 800 μm in diameter. Similarly, the TMA analysis of human HCCs revealed loss of all four marker proteins in the majority of tumourous tissue samples. Preservation of LYVE-1 expression showed a significant correlation with low grading (G1). In corresponding peri-tumourous liver tissue, loss of all marker proteins was seen in a minor proportion of cases (34%) while the majority of cases retained expression of at least one of the marker proteins. Loss of stabilin-2 expression in peri-tumourous liver tissue of patients with HCC was significantly less likely to occur (38%) than loss of the other marker proteins (63-95%) and it was associated with significantly longer tumour-specific (P = 0.0523) and overall (P = 0.0338) survival. Loss of stabilin-2 may enhance survival in HCC by preventing endothelial-tumour cell adhesive interactions and microvascular invasion.
CONCLUSIONS: In summary, endothelial transdifferentiation is a major pathogenic event in HCC development indicating a switch from vessel co-option/intussusceptive angiogenesis to sprouting angiogenesis.

Bhawan J, Silva C, Taungjaruwinai WM
Inconsistent immunohistochemical expression of lymphatic and blood endothelial cell markers in cutaneous lymphangiomas.
J Cutan Pathol. 2013; 40(9):801-6 [PubMed] Related Publications
PURPOSE: We sought to describe expression of the immunohistochemical markers, CD31, D2-40 and LYVE-1 (lymphatic vessel hyaluronan receptor-1), that may assist in differentiating cutaneous lymphangioma and cutaneous hemangioma.
METHODS: Immunohistochemical staining of lymphangioma and hemangioma specimens was completed with CD31, D2-40 and LYVE-1 antibodies.
RESULTS: Thirty-three examples of lymphangioma and 13 examples of hemangioma were evaluated. CD31 was positive in 91% of lymphangioma and 100% of hemangioma (sensitivity 0.91, 95% confidence interval 0.75-0.98; specificity 0, 95% confidence interval 0-0.28). D2-40 was positive in 54% of lymphangioma and 23% in hemangioma (sensitivity 0.50 95% confidence interval 0.32-0.68; specificity 0.50 95% confidence interval 0.28-0.72). LYVE-1 was positive in 6% in lymphangioma and 15% hemangioma (sensitivity 0.06 95% confidence interval 0.01-0.22, specificity 0.85 95% confidence interval 0.54-0.97).
CONCLUSIONS: Due to the similar embryonic origins, it is unlikely that a single marker may accurately differentiate the lymphangioma from hemangioma. A combination of immunohistochemical stains such CD31, D2-40 and LYVE-1 testing may potentially increase the diagnostic accuracy in differentiating lymphangioma from hemangioma. However, our findings suggest that there is no advantage in performing immunohistochemical staining to differentiate lymphangioma from hemangioma.

Majumder M, Xin X, Lala PK
A practical and sensitive method of quantitating lymphangiogenesis in vivo.
Lab Invest. 2013; 93(7):779-91 [PubMed] Related Publications
To address the inadequacy of current assays, we developed a directed in vivo lymphangiogenesis assay (DIVLA) by modifying an established directed in vivo angiogenesis assay. Silicon tubes (angioreactors) were implanted in the dorsal flanks of nude mice. Tubes contained either growth factor-reduced basement membrane extract (BME)-alone (negative control) or BME-containing vascular endothelial growth factor (VEGF)-D (positive control for lymphangiogenesis) or FGF-2/VEGF-A (positive control for angiogenesis) or a high VEGF-D-expressing breast cancer cell line MDA-MD-468LN (468-LN), or VEGF-D-silenced 468LN. Lymphangiogenesis was detected superficially with Evans Blue dye tracing and measured in the cellular contents of angioreactors by multiple approaches: lymphatic vessel endothelial hyaluronan receptor-1 (Lyve1) protein (immunofluorescence) and mRNA (qPCR) expression and a visual scoring of lymphatic vs blood capillaries with dual Lyve1 (or PROX-11 or Podoplanin)/Cd31 immunostaining in cryosections. Lymphangiogenesis was absent with BME, high with VEGF-D or VEGF-D-producing 468LN cells and low with VEGF-D-silenced 468LN. Angiogenesis was absent with BME, high with FGF-2/VEGF-A, moderate with 468LN or VEGF-D and low with VEGF-D-silenced 468LN. The method was reproduced in a syngeneic murine C3L5 tumor model in C3H/HeJ mice with dual Lyve1/Cd31 immunostaining. Thus, DIVLA presents a practical and sensitive assay of lymphangiogenesis, validated with multiple approaches and markers. It is highly suited to identifying pro- and anti-lymphangiogenic agents, as well as shared or distinct mechanisms regulating lymphangiogenesis vs angiogenesis, and is widely applicable to research in vascular/tumor biology.

Frewer NC, Ye L, Sun PH, et al.
Potential implication of IL-24 in lymphangiogenesis of human breast cancer.
Int J Mol Med. 2013; 31(5):1097-104 [PubMed] Related Publications
Lymphangiogenesis is involved in the dissemination of malignant cells from solid tumours to regional lymph nodes and possibly to various distant sites. Lymphangiogenesis is regulated by vascular endothelial growth factor (VEGF)-C and VEGF-D. Interleukin (IL)-24 is known as a cytokine with potent antitumour and tumour-suppressive activity which functions through its receptor (IL-22R). Expression of IL-24 has been shown to be reduced in breast cancer, and the reduced expression is associated with lymphatic metastases and a poor prognosis. However, the involvement of IL-24 in lymphangiogenesis during lymphatic metastasis remains unclear. The aim of the present study was to determine whether there is an association between IL-24, IL-22R and lymphangiogenic factors and markers in breast cancer. Analysis of IL-24, IL-22R and lymphangiogenic factors in malignant breast tissue samples (n=127) revealed a correlation between increased expression of lymphangiogenic markers (podoplanin, Prox-1 and LYVE-1) and reduced levels of IL-24 and IL-22R. Samples stained with a high degree of positivity for lymphangiogenic factors and markers whereas staining for IL-24 was weak. In vitro assays showed that the average perimeter length of microtubules formed by endothelial cells treated with IL-24 was significantly reduced compared to the control. The growth of endothelial cells was significantly reduced when exposed to a high concentration of IL-24 (250 ng/ml). Treatment of HECV cells with IL-24 resulted in significantly reduced expression of VEGF-C (P<0.05) and VEGF-D (P<0.001). In conclusion, reduced expression of IL-24 and IL-22R in breast cancer is correlated with increased expression of specific lymphangiogenic markers. IL-24 suppressed in vitro growth and microtubule formation of endothelial cells. IL-24 may downregulate the expression of lymphangiogenic markers and factors although further research is required. This suggests that IL-24 plays a profound role in suppressing tumour lymphangiogenesis, thereby, reducing the likelihood of cancer metastasis via the lymphatic route.

Ozmen F
Response letter regarding the interpretation of gene expression data.
World J Gastroenterol. 2013; 19(10):1669-70 [PubMed] Free Access to Full Article Related Publications
This is a response letter to Verna E's comments regarding our previous manuscript published last year in the World Journal of Gastroenterology entitled "Relationship between LYVE-1, VEGFR-3 and CD44 gene expressions and lymphatic metastasis in gastric cancer", which evaluated the relationship between these expression levels and clinicopathological parameters (Ozmen F et al, World J Gastroenterology 2011; 17: 3220-3228). The mean values for lymphatic vessel endothelial hyaluronan receptor-1, CD44 and vascular endothelial growth factor receptor-3 expression (represented as 2(-ΔΔCt)) were 1.13, 1.24 and 1.17, respectively, suggesting an increase in gene expression in tumor tissue compared to normal tissue. Despite the increase in gene expression in the cancer tissues (2(-ΔΔCt) > 1), only some of the results reached statistical significance, which was thoroughly discussed in our paper. In the present letter, we report that his comments are flawed and result in confusion. Therefore, we herein provide more explanation regarding gene expression in gastric cancer. We hope that this letter will address Verna E's misunderstandings.

Liu H, Han D, Liu Y, et al.
Harmine hydrochloride inhibits Akt phosphorylation and depletes the pool of cancer stem-like cells of glioblastoma.
J Neurooncol. 2013; 112(1):39-48 [PubMed] Related Publications
Harmine hydrochloride (Har-hc), a derivative from Harmine which is a natural extractive from plants, has been considered for treatment of kinds of cancers and cerebral diseases. In this study, we found that Har-hc clearly decreased cell viability, induced apoptosis and inhibited Akt phosphorylation in glioblastoma cell lines. Moreover, Har-hc had the ability to inhibit self-renewal and promote differentiation of glioblastoma stem like cells (GSLCs) accompanied by inhibition of Akt phosphorylation. Especially, we demonstrated that Har-hc inhibited neurosphere formation of human primary GSLCs. In vivo test also confirmed Har-hc decreased the tumorigenicity of GSLCs. Thus we conclude that Har-hc has potent anti-cancer effects in glioblastoma cells, which is at least partially via inhibition of Akt phosphorylation. Administration of Har-hc may act as a new approach to glioblastoma treatment.

Perez R, Schally AV, Vidaurre I, et al.
Antagonists of growth hormone-releasing hormone suppress in vivo tumor growth and gene expression in triple negative breast cancers.
Oncotarget. 2012; 3(9):988-97 [PubMed] Free Access to Full Article Related Publications
This study evaluated the effects of a modern antagonistic analog of GHRH on tumor growth and on expression of inflammatory cytokine genes in two models of human triple negative breast cancers (TNBC). The TNBC subtype is refractory to the treatment options available for other hormone-independent breast cancers. Inflammatory cytokines play a major role in the cellular signaling associated with breast cancer pathogenesis and enhance epithelial-mesenchymal transitions (EMT), drug resistance, and metastatic potential. Growth hormone-releasing hormone (GHRH) is a hypothalamic neuropeptide which regulates the synthesis and release of growth hormone by the pituitary and is an autocrine/paracrine growth factor for multiple human cancers. The effects of analogs of GHRH on tumoral cytokine expression have not been previously investigated. Animals bearing xenografts of the human TNBC cell lines, HCC1806 and MX-1, were treated with MIA-602, an antagonistic analog of GHRH. Treatment with MIA-602 significantly reduced tumor growth. We quantified transcript levels of the genes for several inflammatory cytokines. Expression of INFγ, IL-1α, IL-4, IL-6, IL-8, IL-10, and TNFα, was significantly reduced by treatment with MIA-602. We conclude that treatment of TNBC with GHRH antagonists reduces tumor growth through an action mediated by tumoral GHRH receptors and produces a suppression of inflammatory cytokine signaling. Silencing of GHRH receptors in vitro with siRNA inhibited the expression of GHRH-R genes and inflammatory cytokine genes in HCC1806 and MX-1 cells. Further studies on GHRH antagonists may facilitate the development of new strategies for the treatment of resistant cancers.

Verna E
More attention should be paid on the interpretation of gene expression data.
World J Gastroenterol. 2012; 18(24):3181-2 [PubMed] Free Access to Full Article Related Publications
Molecular profiling of gene expression is important for determining signatures in cancer progression and diagnosis. For this purpose, polymerase chain reaction-based techniques are preferentially used as a feasible and sensitive approach. Nevertheless, when relative quantitative analyses are performed on gene expression, the interpretation of mathematical equations must be carefully done. This letter to the editor is focused on recently published gene expression data in World Journal of Gastroenterology by Ozmen et al demonstrating increased levels of LYVE-1, VEGFR-3 and CD44 genes in gastric cancer samples compared to non-neoplastic gastric tissues. However, there are major concerns about misinterpretation of the gene expression data obtained with the 2(-ΔΔCt) relative quantitative method. In the study, 2(-ΔΔCt) values calculated for many samples were smaller than 1 (2(-ΔΔCt) < 1) which indicate decreased levels of LYVE-1, VEGFR-3 and CD44 gene expression in the gastric cancer tissues. This unfortunate mistake is an important example showing how a simple error in the interpretation of relative-quantitative gene expression data may result in misleading scientific conclusions. In this letter, a brief explanation of the 2(-ΔΔCt) method is given. In addition, the importance of technical quality and interpretation in gene expression studies is discussed.

Lesma E, Eloisa C, Isaia E, et al.
Development of a lymphangioleiomyomatosis model by endonasal administration of human TSC2-/- smooth muscle cells in mice.
Am J Pathol. 2012; 181(3):947-60 [PubMed] Related Publications
Lymphangioleiomyomatosis (LAM) is an interstitial lung disease characterized by invasion and proliferation of abnormal smooth muscle (ASM) cells in lung parenchyma and axial lymphatics. LAM cells bear mutations in tuberous sclerosis (TSC) genes. TSC2(-/-) ASM cells, derived from a human renal angiomyolipoma, require epidermal growth factor (EGF) for proliferation. Blockade of EGF receptors (EGFR) causes cell death. TSC2(-/-) ASM cells, previously labeled with PKH26-GL dye, were endonasally administered to 5-week-old immunodeficient female nude mice, and 4 or 26 weeks later anti-EGFR antibody or rapamycin was administered twice a week for 4 consecutive weeks. TSC2(-/-) ASM cells infiltrated lymph nodes and alveolar lung walls, causing progressive destruction of parenchyma. Parenchymal destruction was efficiently reversed by anti-EGFR treatment and partially by rapamycin treatment. Following TSC2(-/-) ASM cell administration, lymphangiogenesis increased in lungs as indicated by more diffuse LYVE1 expression and high murine VEGF levels. Anti-EGFR antibody and rapamycin blocked the increase in lymphatic vessels. This study shows that TSC2(-/-) ASM cells can migrate and invade lungs and lymph nodes, and anti-EGFR antibody is more effective than rapamycin in promoting lung repair and reducing lymphangiogenesis. The development of a model to study metastasis by TSC cells will also help to explain how they invade different tissues and metastasize to the lung.

Newman B, Lose F, Kedda MA, et al.
Possible genetic predisposition to lymphedema after breast cancer.
Lymphat Res Biol. 2012; 10(1):2-13 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Known risk factors for secondary lymphedema only partially explain who develops lymphedema following cancer, suggesting that inherited genetic susceptibility may influence risk. Moreover, identification of molecular signatures could facilitate lymphedema risk prediction prior to surgery or lead to effective drug therapies for prevention or treatment. Recent advances in the molecular biology underlying development of the lymphatic system and related congenital disorders implicate a number of potential candidate genes to explore in relation to secondary lymphedema.
METHODS AND RESULTS: We undertook a nested case-control study, with participants who had developed lymphedema after surgical intervention within the first 18 months of their breast cancer diagnosis serving as cases (n=22) and those without lymphedema serving as controls (n=98), identified from a prospective, population-based, cohort study in Queensland, Australia. TagSNPs that covered all known genetic variation in the genes SOX18, VEGFC, VEGFD, VEGFR2, VEGFR3, RORC, FOXC2, LYVE1, ADM, and PROX1 were selected for genotyping. Multiple SNPs within three receptor genes, VEGFR2, VEGFR3, and RORC, were associated with lymphedema defined by statistical significance (p<0.05) or extreme risk estimates (OR <0.5 or >2.0).
CONCLUSIONS: These provocative, albeit preliminary, findings regarding possible genetic predisposition to secondary lymphedema following breast cancer treatment warrant further attention for potential replication using larger datasets.

Ozmen F, Ozmen MM, Ozdemir E, et al.
Relationship between LYVE-1, VEGFR-3 and CD44 gene expressions and lymphatic metastasis in gastric cancer.
World J Gastroenterol. 2011; 17(27):3220-8 [PubMed] Free Access to Full Article Related Publications
AIM: To investigate the expression levels of lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1), vascular endothelial growth factor receptor-3 (VEGFR-3) and CD44 genes and the relationship between their levels and clinicopathological parameters in gastric cancer.
METHODS: Tissue samples were obtained from 33 patients (8 females) with gastric cancer. mRNA levels of LYVE-1, VEGFR-3 and CD44 in normal and tumor tissues were quantitatively measured using real time polymerase chain reaction. The results were correlated with lymph node metastasis, histological type and differentiation of the tumor, T-stage, and presence of vascular, perineural and lymphatic invasions. The distribution of molecules in the tissue was evaluated using immunohistochemistry.
RESULTS: LYVE-1, CD44 and VEGFR-3 gene expression levels were significantly higher in gastric cancer than in normal tissue. While there was no correlation between gene expressions and clinicopathologic features such as histologic type, differentiation and stage, gene expression levels were found to be increased in conjunction with positive lymph node/total lymph node ratio and the presence of perineural invasion. A significant correlation was also found between LYVE-1 and CD44 over-expressions and perineural invasion and lymph node positivity in gastric cancers. When the distribution of LYVE-1 antibody-stained lymphatic vessels in tissue was evaluated, lymphatic vessels were located intra-tumorally in 13% and peri-tumorally in 27% of the patients. Moreover, lymph node metastases were also positive in all patients with LYVE-1-staining.
CONCLUSION: LYVE-1, VEGFR-3 and CD44 all play an important role in lymphangiogenesis, invasion and metastasis. LYVE-1 is a perfectly reliable lymphatic vessel marker and useful for immunohistochemistry.

Chaudary N, Milosevic M, Hill RP
Suppression of vascular endothelial growth factor receptor 3 (VEGFR3) and vascular endothelial growth factor C (VEGFC) inhibits hypoxia-induced lymph node metastases in cervix cancer.
Gynecol Oncol. 2011; 123(2):393-400 [PubMed] Related Publications
OBJECTIVES: We have examined the role of VEGFC/VEGFR3 signaling in lymph node metastasis and growth of orthotopic human ME180 and SiHa cervical xenograft models following exposure to hypoxia. Our previous studies showed that growth of these tumors under conditions of cyclic hypoxia increased nodal metastasis.
METHODS: Mice bearing orthotopic tumors were subjected to cyclic hypoxia at 7% O(2)/air 10min cycles 4h/day/2weeks. Knockdown of vegfc was carried out by shRNA and inhibition of VEGFR3 was conducted by blocking antibodies for the mouse and human proteins. VEGFR3 protein expression was detected by Western blotting. Immunohistochemical staining was used to assess CA9, CD31, LYVE1 and Ki67 labeling. Gene expression was determined by real time PCR.
RESULTS: Knock down of vegfc or inhibition of VEGFR3 with blocking antibody reduced metastases under normoxic and cyclic hypoxia conditions. A reduction in lymphatics and blood vessel formation and a decrease in tumor cell proliferation was observed following vegfc knockdown and VEGFR3 inhibition. VEGFR3 expression was upregulated at the mRNA and protein levels following hypoxia.
CONCLUSIONS: Collectively, our results indicate that anti-VEGFR3 antibody inhibits vegfc-induced tumor lymphangiogenesis and metastasis and that vegfc knockdown in the tumor cells causes a similar inhibitory effect on lymph node metastasis. These results suggest that the effects of vegfc/VEGFR3 on the progression of tumor cells to form lymph node metastases occur primarily under an hypoxic tumor microenvironment.

Keichel S, Barcena de Arellano ML, Reichelt U, et al.
Lymphangiogenesis in deep infiltrating endometriosis.
Hum Reprod. 2011; 26(10):2713-20 [PubMed] Related Publications
BACKGROUND: In patients diagnosed with deep infiltrating endometriosis (DIE), foci of endometriosis are detected in mesorectal lymph nodes (LNs) after segmental bowel resection and in pelvic sentinel LNs. Lymph vessels (LVs) seem to be the possible routes for the dissemination of endometriotic cells from DIE-lesions to LN. Therefore, we conducted a study to investigate the occurrence and density of LV and lymphangiogenic growth factors in DIE.
METHODS: Included in this study were 38 premenopausal women who underwent surgery due to symptomatic rectovaginal DIE. In order to identify LV, immunohistochemical analysis with anti-Podoplanin (D2-40), LYVE-1 and Prox-1 was performed. Furthermore, the expression of VEGF-C and VEGF-D in endometriotic tissue was investigated.
RESULTS: LV density (LVD) of DIE lesions was significantly higher compared with healthy corresponding tissue. All LV makers could be detected, and the density of LYVE-1- or Prox-1-positive LV was significantly higher than that of D2-40-positive LV. Endometriotic epithelial cells and stromal cells showed a moderate to strong VEGF-C and VEDF-D expression.
CONCLUSIONS: DIE lesions have lymphangiogenic properties, probably leading to endometriosis-like cells in lymphatic vessels and LNs featuring a loco-regional disease.

Naidu R, Har YC, Taib NA
Analysis of peptidyl-propyl-cis/trans isomerase 1 (PIN1) gene -842(G > C) and -667(T > C) polymorphic variants in relation to breast cancer risk and clinico-pathological parameters.
Scand J Clin Lab Invest. 2011; 71(6):500-6 [PubMed] Related Publications
BACKGROUND: The purpose of this study was to investigate the association between the peptidyl-propyl-cis/trans isomerase 1 (PIN1) -842(G > C) and -667(T > C) polymorphic variants and breast cancer risk among Malaysian ethnic groups namely the Malays, Chinese and Indians, as well as clinico-pathological characteristics of the patients.
PATIENTS AND METHODS: The polymerase chain reaction-restriction fragment length polymorphism was used to genotype 387 breast cancer patients and 252 normal and healthy women who had no history of any malignancy.
RESULTS: The distribution of -842(G > C) and -667(T > C) genotypes and alleles frequencies between breast cancer cases and normal individuals showed lack of statistical significance among the Malays (p > 0.05), Chinese (p > 0.05) and Indians (p > 0.05), respectively. Multivariate logistic regression analysis showed that the Malay, Chinese and Indian women who were -842CC homozygotes (p = 0.198, 0.089, 0.620), -842GC heterozygotes (p = 0.492, 0.176, 0.377) and -842C allele carriers (P = 0.226, 0.059, 0.669), respectively, were not associated with breast cancer risk. Furthermore Malay, Chinese and Indian women who were heterozygous (p = 0.777, 0.319, 0.710) and homozygous (p = 0.864, 0.986, 0.954) for -667C allele or carriers of -667C allele (p = 0.977, 0.915, 0.880), respectively, were not associated with an increased risk of breast cancer. None of the -842C and -667C allele genotypes were significantly associated with the clinico-pathological characteristics.
CONCLUSION: Our findings suggest that the polymorphic variants of -842(G > C) and -667(T > C) genes may not appear to have an influence on breast cancer risk among Malaysian Malay, Chinese and Indian women.

Lin WH, Martin JL, Marsh DJ, et al.
Involvement of insulin-like growth factor-binding protein-3 in the effects of histone deacetylase inhibitor MS-275 in hepatoma cells.
J Biol Chem. 2011; 286(34):29540-7 [PubMed] Free Access to Full Article Related Publications
Insulin-like growth factor-binding protein-3 (IGFBP-3) expression is frequently suppressed in liver cancers and can be reactivated by histone deacetylase (HDAC) inhibition. This study examined the role of IGFBP-3 in mediating the effects of the HDAC inhibitor MS-275 in liver cancer cells and identified IGFBP-3-dependent proteins that regulate proliferation and migration. In HepG2 cells, MS-275 inhibited DNA synthesis, cell cycle activity, and cell viability concomitantly with increased binding of acetylated histone H3 to IGFBP-3 promoter sequences and induction of IGFBP-3 expression. IGFBP-3 down-regulation by siRNA significantly reversed the inhibition of cell viability and DNA synthesis by MS-275, indicating an intermediary role for IGFBP-3. Induction of the cyclin-dependent kinase inhibitor p21 by MS-275 was attenuated by IGFBP-3 down-regulation, providing an explanation for IGFBP-3-dependent effects of MS-275 on cell cycle activity. In contrast, MS-275 stimulated HepG2 cell migration, an effect also inhibited by IGFBP-3 down-regulation. Among genes whose induction by MS-275 was attenuated by IGFBP-3 down-regulation, LYVE1 and THBS2 (thrombospondin-2) were identified as mediators of IGFBP-3-dependent effects of MS-275. Silencing of either protein had no effect on the inhibition of HepG2 viability by MS-275 but reversed its stimulatory effect on cell migration. We conclude that among genes up-regulated by MS-275, IGFBP-3 is a key mediator of effects on hepatoma cell growth and migration, involving IGFBP-3-dependent proteins p21 (proliferation) and LYVE1 and THBS2 (migration). The enhanced cell motility that accompanies reactivation of IGFBP-3 expression in liver cancer by HDAC inhibition suggests the possibility of increased metastatic spread despite inhibited cell proliferation.

Ching HC, Naidu R, Seong MK, et al.
Integrated analysis of copy number and loss of heterozygosity in primary breast carcinomas using high-density SNP array.
Int J Oncol. 2011; 39(3):621-33 [PubMed] Related Publications
Breast cancer is a heterogeneous disease, marked by extensive chromosomal aberrations. In this study, we aimed to explicate the underlying chromosomal copy number (CN) alterations and loss of heterozygosity (LOH) implicated in a cohort of Malaysian hospital-based primary breast carcinoma samples using a single nucleotide polymorphism (SNP) array platform. The analysis was conducted by hybridizing the extracted DNA of 70 primary breast carcinomas and 37 normal peripheral blood samples to the Affymetrix 250K Sty SNP arrays. Locus-specific CN aberrations and LOH were statistically summarized using the binary segmentation algorithm and hidden Markov model. Selected genes from the SNP array analysis were also validated using quantitative real-time PCR. The merging of CN and LOH data fabricated distinctive integrated alteration profiles, which were comprised of finely demarcated minimal sites of aberrations. The most prevalent gains (≥ 30%) were detected at the 8q arm: 8q23.1, 8q23.3, 8q24.11, 8q24.13, 8q24.21, 8q24.22, 8q24.23 and 8q24.3, whilst the most ubiquitous losses (≥ 20%) were noted at the 8p12, 8p21.1, 8p21.2, 8p21.1-p21.2, 8p21.3, 8p22, 8p23.1, 8p23.1‑p23.2, 8p23.3, 17p11.2, 17p12, 17p11.2-p12, 17p13.1 and 17p13.2 regions. Copy-neutral LOH was characterized as the most prevailing LOH event, in which the most frequent distributions (≥ 30%) were revealed at 3p21.31, 5q33.2, 12q24.12, 12q24.12‑q24.13 and 14q23.1. These findings offer compre-hensive genome-wide views on breast cancer genomic changes, where the most recurrent gain, loss and copy-neutral LOH events were harboured within the 8q24.21, 8p21.1 and 14q23.1 loci, respectively. This will facilitate the uncovering of true driver genes pertinent to breast cancer biology and the develop-ment of prospective therapeutics.

Naidu R, Har YC, Taib NA
Genetic polymorphisms of TP53-binding protein 1 (TP53BP1) gene and association with breast cancer risk.
APMIS. 2011; 119(7):460-7 [PubMed] Related Publications
In the present study, we evaluated the association between the TP53BP1 Glu353Asp and T-885G polymorphisms and breast cancer risk as well as with the clinicopathological characteristics of the patients. Genotyping of these polymorphisms was performed on 387 breast cancer patients and 252 normal and healthy women who had no history of any malignancy using PCR-RFLP method in a hospital-based Malaysian population. Breast cancer risk was not observed among women who were heterozygous (OR(adj) = 0.887; 95% CI, 0.632-1.245) or homozygous (OR(adj) = 1.083; 95% CI, 0.595-1.969) for Asp allele, and those carriers of Asp allele (OR(adj) = 0.979; 95% CI, 0.771-1.243). Similarly, women who were TG heterozygotes (OR(adj) = 1.181; 95% CI, 0.842-1.658) or GG homozygotes (OR(adj) = 1.362; 95% CI, 0.746-2.486) and carriers of G allele (OR(adj) = 1.147; 95% CI, 0.903-1.458) were not associated with increased risk of breast cancer. Asp allele genotype was significantly associated with ER negativity (p = 0.0015) and poorly differentiated tumours (p = 0.008), but G allele genotype was not associated with the clinicopathological characteristics. In conclusion, Glu353Asp and T-885G polymorphic variants might not have an influence on breast cancer risk, thus might not be potential candidates for cancer susceptibility. Glu353Asp variant might be associated with tumour aggressiveness as defined by its association with ER negativity and poorly differentiated tumours.

Kim HS, Kim do H, Kim JY, et al.
Microarray analysis of papillary thyroid cancers in Korean.
Korean J Intern Med. 2010; 25(4):399-407 [PubMed] Free Access to Full Article Related Publications
BACKGROUND/AIMS: Papillary thyroid cancer (PTC) is the most common malignancy of the thyroid gland. It involves several molecular mechanisms. The BRAF V600E mutation has been identified as the most common genetic abnormality in PTC. Moreover, it is known to be more prevalent in Korean PTC patients than in patients from other countries. We investigated distinct genetic profiles in Korean PTC through cDNA microarray analysis.
METHODS: Transcriptional profiles of five PTC samples and five paired normal thyroid tissue samples were generated using cDNA microarrays. The tumors were genotyped for BRAF mutations. The results of the cDNA microarray gene expression analysis were confirmed by real-time PCR and immunohistochemistry analysis of 35 PTC patients.
RESULTS: Four of the five patients whose PTC tissues were subjected to microarray analysis were found to carry the BRAF V600E mutation. Microarrays analysis of the five PTC tissue samples showed the expression of 96 genes to be increased and that of 16 genes decreased. Real-time reverse transcription-polymerase chain reaction (RT-PCR) confirmed increased expression of SLC34A2, TM7SF4, COMP, KLK7, and KCNJ2 and decreased expression of FOXA2, SLC4A4, LYVE-1, and TFCP2L1 in PTC compared with normal tissue. Of these genes, TFCP2L1, LYVE-1, and KLK7 were previously unidentified in PTC microarray analysis. Notably, Foxa2 activity in PTC was reduced, as shown by its cytoplasmic localization, in immunohistochemical analyses.
CONCLUSIONS: These findings demonstrate both similarities and differences between our results and previous reports. In Korean cases of PTC, Foxa2 activity was reduced with its cytoplasmic accumulation. Further studies are needed to confirm the relationship between FOXA2 and BRAF mutations in Korean cases of PTC.

Le Huu AR, Jokinen CH, Rubin BP, et al.
Expression of prox1, lymphatic endothelial nuclear transcription factor, in Kaposiform hemangioendothelioma and tufted angioma.
Am J Surg Pathol. 2010; 34(11):1563-73 [PubMed] Related Publications
Kaposiform hemangioendothelioma (KHE) and tufted angioma (TA) are rare tumors mainly occurring in early childhood. Our recent results showed that ectopic overexpression of human Prox1 gene, a lymphatic endothelial nuclear transcription factor, promoted an aggressive behavior in 2 murine models of KHE. This dramatic Prox1-induced phenotype prompted us to investigate immunohistochemical staining pattern of Prox1, podoplanin (D2-40), LYVE-1, and Prox1/CD34 as well as double immunofluorescent staining pattern of LYVE-1/CD31 in KHE and TA, compared with other pediatric vascular tumors. For this purpose, we examined 75 vascular lesions: KHE (n=18), TA (n=13), infantile hemangioma (n=13), pyogenic granuloma (n=18), and granulation tissue (n=13). Overall, KHE and TA shared an identical endothelial immunophenotype: the neoplastic spindle cells were Prox1, podoplanin, LYVE-1, CD31, and CD34, whereas endothelial cells within glomeruloid foci were Prox1, podoplanin, LYVE-1, CD31, and CD34. The lesional cells of all infantile hemangiomas and pyogenic granulomas were negative for Prox1 in the presence of positive internal control. These findings provide immunophenotypic evidence to support a preexisting notion that KHE and TA are closely related, if not identical. Overall, our results show, for the first time, that Prox1 is an immunohistochemical biomarker helpful in confirming the diagnosis of KHE/TA and in distinguishing it from infantile hemangioma and pyogenic granuloma.

Moussai D, Mitsui H, Pettersen JS, et al.
The human cutaneous squamous cell carcinoma microenvironment is characterized by increased lymphatic density and enhanced expression of macrophage-derived VEGF-C.
J Invest Dermatol. 2011; 131(1):229-36 [PubMed] Related Publications
Metastases from primary cutaneous squamous cell carcinoma (SCC) account for the majority of the ∼10,000 non-melanoma skin cancer deaths in the United States annually. We studied lymphangiogenesis in human SCC because of the potential link to metastasis. SCC samples were stained for lymphatic endothelial vessel marker LYVE-1 and positive cells were counted and compared with cells in normal skin. Gene set enrichment analysis and reverse transcription (RT)-PCR were performed on SCC, on adjacent non-tumor-bearing skin, and on normal skin to determine the differential expression of lymphangiogenesis-associated genes. Laser capture microdissection (LCM) was performed to isolate tumor cells and tumor-associated inflammatory cells for further gene expression analysis. Immunofluorescence was performed to determine the source of vascular endothelial growth factor-C (VEGF-C) in the tumor microenvironment. We found increased lymphatic density and reorganized lymphatic endothelial vessels in the dermis immediately adjacent to SCC nests. RT-PCR confirmed the presence of VEGF-C in skin immediately adjacent to SCC. LCM confirmed the increased expression of VEGF-C, the SCC inflammatory infiltrate. The presence of CD163(+)/CD68(+)/VEGFC(+) cells and absence of VEGF-C expression by CD3(+) or CD11C(+) cells suggested that VEGF-C is derived from tumor-associated macrophages. Clarification of mechanisms governing SCC-mediated lymphangiogenesis may identify potential targets for therapeutic intervention against aggressive or inoperable disease.

Naidu R, Har YC, Taib NA
Glyoxalase I Ala111Glu gene polymorphism: No association with breast cancer risk but correlated with absence of progesterone receptor.
Pathol Int. 2010; 60(9):614-20 [PubMed] Related Publications
The aim of the present study was to evaluate the association between the Glyoxalase I (GLOI) Ala111Glu polymorphism and breast cancer risk among the major Malaysian ethnic groups, the Malays, Chinese and Indians, as well as clinico-pathological characteristics of these patients. Genotyping of GLOI gene was performed on blood samples obtained from 387 patients and 252 normal healthy women who had no history of any malignancy using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The genotype and allele frequencies of GLOI polymorphism were not significantly different between the patients and normal individuals among the Malays (P= 0.721, 0.402), Chinese (P= 0.208, 0.079) and Indians (P= 0.612, 0.349), respectively. The Malay, Chinese and Indian women who were Glu/Glu homozygotes (P= 0.419, 0.093, 0.367), Ala/Glu heterozygotes (P= 0.648, 0.182, 0.402) and carriers of Glu allele (P= 0.402, 0.079, 0.349), respectively, were not associated with breast cancer risk. The Glu allele genotype was significantly associated with absence of progesterone receptor (P= 0.036). Thus, the polymorphic variant of the GLOI gene might not be a useful genetic marker to identify Malaysian Malay, Chinese or Indian women who could be at greater risk of developing breast cancer.

Girling JE, Donoghue JF, Lederman FL, et al.
Vascular endothelial growth factor-D over-expressing tumor cells induce differential effects on uterine vasculature in a mouse model of endometrial cancer.
Reprod Biol Endocrinol. 2010; 8:84 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: It has been hypothesised that increased VEGF-D expression may be an independent prognostic factor for endometrial cancer progression and lymph node metastasis; however, the mechanism by which VEGF-D may promote disease progression in women with endometrial cancer has not been investigated. Our aim was to describe the distribution of lymphatic vessels in mouse uterus and to examine the effect of VEGF-D over-expression on these vessels in a model of endometrial cancer. We hypothesised that VEGF-D over-expression would stimulate growth of new lymphatic vessels into the endometrium, thereby contributing to cancer progression.
METHODS: We initially described the distribution of lymphatic vessels (Lyve-1, podoplanin, VEGFR-3) and VEGF-D expression in the mouse uterus during the estrous cycle, early pregnancy and in response to estradiol-17beta and progesterone using immunohistochemistry. We also examined the effects of VEGF-D over-expression on uterine vasculature by inoculating uterine horns in NOD SCID mice with control or VEGF-D-expressing 293EBNA tumor cells.
RESULTS: Lymphatic vessels positive for the lymphatic endothelial cell markers Lyve-1, podoplanin and VEGFR-3 profiles were largely restricted to the connective tissue between the myometrial circular and longitudinal muscle layers; very few lymphatic vessel profiles were observed in the endometrium. VEGF-D immunostaining was present in all uterine compartments (epithelium, stroma, myometrium), although expression was generally low. VEGF-D immunoexpression was slightly but significantly higher in estrus relative to diestrus; and in estradiol-17beta treated mice relative to vehicle or progesterone treated mice. The presence of VEGF-D over-expressing tumor cells did not induce endometrial lymphangiogenesis, although changes were observed in existing vessel profiles. For myometrial lymphatic and endometrial blood vessels, the percentage of profiles containing proliferating endothelial cells, and the cross sectional area of vessel profiles were significantly increased in response to VEGF-D in comparison to control tumor cells. In contrast, no significant changes were noted in myometrial blood vessels. In addition, examples of invading cells or tumor emboli were observed in mice receiving VEGF-D expressing 293EBNA cells.
CONCLUSIONS: These results illustrate that VEGF-D over-expression has differential effects on the uterine vasculature. These effects may facilitate VEGF-D's ability to promote endometrial cancer metastasis and disease progression.

Bhattacharjee RN, Timoshenko AV, Cai J, Lala PK
Relationship between cyclooxygenase-2 and human epidermal growth factor receptor 2 in vascular endothelial growth factor C up-regulation and lymphangiogenesis in human breast cancer.
Cancer Sci. 2010; 101(9):2026-32 [PubMed] Related Publications
Both cyclooxygenase (COX)-2 and human epidermal growth factor receptor (HER)-2 promote breast cancer progression; however, the relationship between the two molecules remains unclear. We utilized human breast cancer tissues and cell lines to examine whether COX-2 and HER-2 played independent or interdependent roles in vascular endothelial growth factor (VEGF)-C up-regulation and lymphangiogenesis. A paired correlation of immunodetectable levels of COX-2, VEGF-C, and HER-2 proteins and lymphovascular density (LVD; D2-40-immunolabeled) in 55 breast cancer specimens revealed a positive correlation between COX-2 and HER-2 irrespective of clinicopathological status. However COX-2 alone positively correlated with LVD. In 10 independent specimens, mRNA levels showed a positive correlation between HER-2 and COX-2 or VEGF-C but not LYVE-1 (lymphovascular endothelial marker). These findings implicate COX-2, but not HER-2, in breast cancer-associated lymphangiogenesis. Manipulation of the COX-2 or HER-2 genes in breast cancer cell lines varying widely in COX-2 and HER-2 expression revealed a direct role of COX-2 and an indirect COX-2 dependent role of HER-2 in VEGF-C up-regulation: (i) high VEGF-C expression in high COX-2/low HER-2 expressing MDA-MB-231 cells was reduced by siRNA-mediated down-regulation of COX-2, but not HER-2; (ii) integration of HER-2 in these cells simultaneously up-regulated COX-2 protein as well as VEGF-C secretion; and (iii) low VEGF-C secretion by high HER-2/low COX-2 expressing SK-BR-3 cells was stimulated by COX-2 overexpression. These findings of the primary role of COX-2 and the COX-2-dependent role of HER-2, if any, in VEGF-C up-regulation and lymphangiogenesis suggest that COX-2 inhibitors may abrogate lymphatic metastasis in breast cancer irrespective of HER-2 status.

Ishii H, Chikamatsu K, Sakakura K, et al.
Primary tumor induces sentinel lymph node lymphangiogenesis in oral squamous cell carcinoma.
Oral Oncol. 2010; 46(5):373-8 [PubMed] Related Publications
The main factor that affects the prognosis of patients with oral squamous cell carcinoma (OSCC) is regional lymph node metastases, which usually spreads first to the sentinel lymph nodes (SLNs). Recent studies have demonstrated that tumor cells in several malignancies can induce lymphangiogenesis in SLNs before metastasizing. To elucidate the mechanisms of tumor dissemination of OSCC, we investigated whether primary tumors induce lymphangiogenesis within SLNs in patients with OSCC. The mRNA expression of lymphatic-specific markers, including VEGFR-3, Prox-1, and LYVE-1 in 23 metastasis-negative SLNs obtained from 10 patients with OSCC, was investigated using a quantitative real-time RT-PCR assay, and compared with control lymph nodes from patients with non-cancerous diseases. In addition, VEGF-C and VEGF-D expressions of the primary tumor were examined by immunohistochemistry. In SLNs, there were highly significant correlations between the three lymphatic markers examined. Interestingly, the level of LYVE-1 expression in SLNs, despite the absence of metastasis, was significantly higher than in control lymph nodes. Moreover, SLNs from patients with VEGF-C-positive tumor showed a significantly higher expression of VEGFR-3 than those from patients with VEGF-C-negative tumor. Our findings suggest that in OSCC, the primary tumor actively induces lymphangiogenesis in SLNs prior to the onset of metastases, and where tumor-derived VEGF-C plays an important role.

Naidu R, Har YC, Taib NA
Polymorphism of FGFR4 Gly388Arg does not confer an increased risk to breast cancer development.
Oncol Res. 2009; 18(2-3):65-71 [PubMed] Related Publications
The genotype analysis of the Gly and Arg allele at codon 388 of fibroblast growth factor receptor-4 (FGFR4) gene was evaluated using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method in a hospital-based Malaysian population. Peripheral blood samples were collected from 387 breast cancer patients and 252 normal and healthy women who had no history of any malignancy. The aim of the present study was to evaluate the association between the FGFR4 Gly388Arg polymorphism and breast cancer risk as well as clinicopathological parameters of the patients. The Gly/Gly, Gly/Arg, Arg/Arg, and Arg allele genotypes were detected in 46.3%, 44.4%, 9.3%, and 53.7% of breast cancer cases, respectively. The distribution of genotype (p = 0.204) and allele (p = 0.086) frequencies of FGFR4 polymorphism were not significantly different between the breast cancer cases and normal individuals. Women who were Arg/ Arg homozygotes (OR = 1.714, 95% CI 0.896-3.278), Gly/Arg heterozygotes (OR = 1.205, 95% CI 0.863-1.683), carriers of Arg allele genotype (OR = 1.269, 95% CI 0.921-1.750), or Arg allele (OR = 1.246, 95% CI 0.970-1.602) were not associated with breast cancer risk. The Arg allele genotype was significantly associated with lymph node metastases (p = 0.001) but not with other clinicopathological parameters. Our findings suggest that the polymorphic variant at codon 388 of FGFR4 gene does not confer increased risk to breast cancer development but it may be a potential genetic marker for tumor prognosis.

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