・Christou CM, Pearce AC, Watson AA, Mistry AR, Pollitt AY, Fenton-May AE, Johnson LA, Jackson DG, Watson SP, O'Callaghan CA. Renal cells activate the platelet receptor CLEC-2 through podoplanin. Biochem J. 2008 Jan 14 [Epub ahead of print]
(PubMed)

・Mahtab EA, Wijffels MC, Van Den Akker NM, Hahurij ND, Lie-Venema H, Wisse LJ, Deruiter MC, Uhrin P, Zaujec J, Binder BR, Schalij MJ, Poelmann RE, Gittenberger-De Groot AC. Cardiac malformations and myocardial abnormalities in podoplanin knockout mouse embryos: Correlation with abnormal epicardial development.Dev Dyn. 2008 Feb 8; [Epub ahead of print]
(PubMed)

ポドプラニンのノックアウトマウスを使った解析の論文。ポドプラニンのノックアウトマウスにおいては、リンパ管の発生異常、肺の低形成による呼吸不全の報告があった。今回は、心外膜の発生にポドプラニンが関与しているということを報告している。

・Kawase A, Ishii G, Nagai K, Ito T, Nagano T, Murata Y, Hishida T, Nishimura M, Yoshida J, Suzuki K, Ochiai A. Podoplanin expression by cancer associated fibroblasts predicts poor prognosis of lung adenocarcinoma. Int J Cancer. 2008 Jun 10. [Epub ahead of print]
(PubMed)

ポドプラニンがfibroblastに発現していることは、以前より知られていた（Toyoshima M. et al., Cancer Res., 1995など）。また、fibrosarcoma細胞のHT1080にも発現が報告されている（Suzuki H. et al., FEBS lett. 2008など）。ポドプラニンがcancer-associated fibroblast (CAFs）に発現していることは、昨年の日本がん転移学会や日本癌学会でも発表が相次いだ（今回のグループの他、富山大、広島大など）。今回の論文は、CAFにおけるポドプラニンの発現が肺腺癌の予後と相関しているという最初の論文である。

加藤らの報告（Tumor Biol., 2005）で、肺癌の中では、腺癌にはほとんどポドプラニンの発現が見られず、扁平上皮癌のみに発現が見られる。しかし、それは癌細胞に関しての記述であった。今回は、癌細胞の周囲の微小環境（microenvironment）に注目し、特に、invasive adenocarcinomaのCAFに発現しているポドプラニンが、肺腺癌患者の予後診断に役立つという点で、興味深い。

Recent studies have reported increased podoplanin expression by cancer cells and stromal cells, but little is known about its expression and biological significance in adenocarcinoma of the lung. We examined podoplanin expression by both cancer cells and stromal cells in 177 consecutive lung adenocarcinoma cases and analyzed relations between podoplanin expression and both clinicopathological factors and outcome. Podoplanin expression was observed on the apical membrane of the cancer cells in only 9 of the 177 (5.1%) cases. By contrast, cancer-associated fibroblasts (CAFs) were found to express podoplanin in 54 cases (30.5%). Podoplanin (+) CAFs were found only in invasive adenocarcinoma and none were found in noninvasive adenocarcinoma. Conventional prognostic factors were significantly correlated with podoplanin expression by CAFs. The univariate analyses and log-rank test showed that podoplanin expression was significantly associated with shorter survival time (p < 0.001 and p < 0.001, respectively). We divided the cases into 3 groups according grade based on the proportion of CAFs expressing podoplanin [a grade 0 group (n = 123), a grade 1 group (n = 36) and a grade 2 group (n = 18)]. The result showed that conventional prognostic factors were significantly correlated with the grade of podoplanin expression by CAFs. Furthermore, the grade 2 group tended to have a shorter survival time than the grade 1 group (p = 0.092). The results of this study highlight the importance of podoplanin expression by CAFs and provide new insights into the biology of the cancer microenvironment in adenocarcinoma of the lung.

・Nakazawa Y, Sato S, Naito M, Kato Y, Mishima K, Arai H, Tsuruo T, Fujita N. Tetraspanin family member CD9 inhibits Aggrus/podoplanin-induced platelet aggregation and suppresses pulmonary metastasis. Blood. 2008 Jun 9. [Epub ahead of print]
(PubMed)

テトラスパニンは4回膜貫通型蛋白である。CD9はそのひとつで、癌転移を抑制することで知られていたが、その詳細なメカニズムはわかっていなかった。今回、CD9が血小板凝集因子／転移促進因子であるポドプラニンの機能を抑制することにより、癌転移を抑えることを示した。ポドプラニンの機能を制御する分子の報告は、これが初めてである。

CD9 has been reported to play a role in tumor metastasis suppression. However, it is not fully understood how CD9 affects the hematogenous spread of tumor cells. To clarify a new mechanism (or mechanisms), we generated HT1080 cells that had been transfected with a CD9-expressing plasmid. Ectopic expression of CD9 in HT1080 cells actually reduced their metastatic ability. CD9 expression reduced lung retention and platelet aggregation activity of the transfectants. Because HT1080 cells express the metastasis-promoting, platelet aggregation-inducing factor Aggrus/podoplanin on their surface, we examined the relationship between CD9 and Aggrus. We discovered that CD9 formed a complex with Aggrus via transmembrane domains 1 and 2 (TM1 and 2) of CD9. Investigation of the interaction revealed that each CD9 and Aggrus interacted homophilically and that they co-localized in low-density membrane fractions. Deleting TM1 and 2 attenuated the ability of CD9 to interact homophilically or to localize in low-density membrane fractions. The expression of CD9-WT, but not CD9 lacking TM1 and 2, attenuated the platelet aggregation and metastasis induced by forced expression of Aggrus in CHO cells. Therefore, CD9 may act as a metastasis suppressor, at least in part, by neutralizing Aggrus-mediated platelet aggregation.

・Atsumi N, Ishii G, Kojima M, Sanada M, Fujii S, Ochiai A. Podoplanin, a novel marker of tumor-initiating cells in human squamous cell carcinoma A431. Biochem Biophys Res Commun. 2008 Jun 5. [Epub ahead of print]
(PubMed)

ポドプラニンが扁平上皮癌で発現していることはよく知られていたが、その機能については不明な点が多い。今回の論文では、ポドプラニンをマーカーとして使うことにより、扁平上皮癌細胞株A431から幹細胞様の特徴を有する腫瘍開始細胞を選び出すことができることを報告しており、Cancer stem cellとポドプラニンとの関係に迫った最初の論文である。

Squamous cell carcinoma (SCC) is a malignant tumor that shows morphologic and phenotypic similarities to normally differentiated squamous epithelium. Thus, it may be an ideal model for seeking a marker of tumor-initiating cells (TICs) based on their morphology. Using the human SCC cell line A431, we found that, as a paradigm of cancer stem cells: (1) podoplanin(+) cells generate both podoplanin(+) and podoplanin(-) cells; (2) podoplanin(-) cells rarely generate podoplanin(+) cells; (3) podoplanin(+) cells have higher colony formation efficiency and tumorigenicity than podoplanin(-) cells; (4) localization and morphology of podoplanin(+) cells in a xenografted tumor derived from podoplanin(+) cells are similar with those in human oral SCC tissue or normal epithelium. Furthermore, podoplanin(+) A431 cells share sonic hedgehog and CD44 expression with stem cells in normal squamous epithelium. Hence, we concluded that podoplanin is a novel marker to enrich TICs with stem-cell-like properties from SCC cell line A431.

・平成20年度（第25回）とやま賞受賞
富山県ひとづくり財団、受賞者紹介、プロフィール、集合写真

富山新聞、北日本新聞、読売新聞、北陸中日新聞、富山新聞、北日本新聞、建設工業新聞

・Hata M, Ueki T, Sato A, Kojima H, Sawa Y. Expression of podoplanin in the mouse salivary glands. Arch Oral Biol. 2008 Mar 11. [Epub ahead of print]
(PubMed)

福岡歯科大学の沢禎彦教授のグループによる報告。唾液腺におけるポドプラニンの発現についての詳細な解析である。

OBJECTIVE: Podoplanin is one of the most highly expressed lymphatic-specific genes. Here, we report the distribution of cells expressing podoplanin in mouse salivary glands. DESIGN: We immunohistochemically investigated the distribution of cells expressing podoplanin in mouse major salivary glands by laser-scanning microscopy. The expression of endothelial cell marker PECAM-1 was tested to discriminate lymphatic endothelium from salivary gland cells, and myoepithelial cells were identified by an antibody for P-cadherin. RESULTS: The podoplanin expression was rarely found in acini of the parotid gland but clearly found at the basal portion of acini in the submandibular and sublingual glands. The number of portion reacted with anti-podoplanin is greater in the sublingual gland than in the submandibular gland. The expression was also found at the basal portion of ducts in all major salivary glands. The P-cadherin expression was rarely found in acini of the parotid gland but found in acini of the sublingual gland and on ducts in parotid and sublingual glands, corresponding to the area of podoplanin expression. CONCLUSIONS: It was suggested that the acinar and myoepithelial cells in the salivary glands have the ability to express podoplanin, and that the expression may be concerned with the mucous saliva excretion.

・Navarro A, Perez RE, Rezaiekhaligh M, Mabry SM, Ekekezie II.

T1{alpha}/PODOPLANIN IS ESSENTIAL FOR CAPILLARY MORPHOGENESIS IN LYMPHATIC ENDOTHELIAL CELLS.

Am J Physiol Lung Cell Mol Physiol. 2008 Jul 25. [Epub ahead of print]
(PubMed)

The lymphatic vasculature functions to maintain tissue perfusion homeostasis. Defects in its formation or disruption of the vessels result in lymphedema, the effective treatment of which is hampered by limited understanding of factors regulating lymph vessel formation. Mice lacking T1alpha/podoplanin, a lymphatic endothelial cell trans-membrane protein, have malformed lymphatic vasculature with lymphedema at birth, but the molecular mechanism for this phenotype is unknown. Here we show, using primary human lung microvascular lymphatic endothelial cells (HMVEC-LLy), that small interfering RNA (siRNA) mediated silence of podoplanin gene expression has the dramatic effect of blocking capillary tube formation in Matrigel(TM). In addition, localization of phosphorylated ezrin/radixin/moesin (ERM) proteins to plasma membrane extensions, an early event in the capillary morphogenic program in lymphatic endothelial cells, is impaired. We find that cells with decreased podoplanin expression fail to properly activate the small GTPase RhoA early (by 30 minutes) after plating on Matrigel(TM), and Rac1 shows a delay in its activation. Further indication podoplanin action is linked to RhoA activation is that use of a cell permeable inhibitor of RhoA inhibited lymphatic endothelial capillary tube formation in the same manner as did podoplanin gene silencing, which was not mimicked by treatment with a Rac1 inhibitor. These data clearly demonstrate that early activation of RhoA in the lymphangiogenic process, which is required for the successful establishment of the capillary network, is dependent on podoplanin expression. To our knowledge, this is the first time that a mechanism has been suggested to explain the role of podoplanin in lymphangiogenesis. Key words: Lymphedema, lymphatics, GTPases, RhoA, Rac1, Matrigel(TM).

・Ito T, Ishii G, Nagai K, Nagano T, Kojika M, Murata Y, Atsumi N, Nishiwaki Y, Miyazaki E, Kumamoto T, Ochiai A.

Low podoplanin expression of tumor cells predicts poor prognosis in pathological stage IB squamous cell carcinoma of the lung, tissue microarray analysis of 136 patients using 24 antibodies.

Lung Cancer. 2008 Jul 24. [Epub ahead of print]
(PubMed)

The aim of this study was to identify clinicopathological and biological prognostic markers for patients who had undergone complete resection of pathological stage IB squamous cell carcinoma (SqCC) of the lung. A total of 136 consecutive stage IB SqCC patients fulfilled eligibility criteria, and their clinicopathological factors were evaluated. Tissue microarrays were also constracted, and immunohistochemical staining with 24 antibodies was performed. Correlations between clinicopathological factors, antibody immunohistochemical reactions, the patients' overall survival (OS) and relapse-free survival (RFS) were evaluated. The univariate analysis showed that 70-year-old and over elderly group had a shorter OS time and RFS time than the younger group (p=0.0086 and p=0.0091, respectively). The univariate analysis for immunohistochemical staining showed that the podoplanin-negative group had a shorter OS time and RFS time than the podoplanin-positive group (p=0.0106 and p=0.0308, respectively). Multivariate analysis revealed a significant correlation between both the 70-year-old and over elderly group and the podoplanin-negative group and poor outcome (OS, p=0.007 and p=0.008, respectively; RFS, p=0.008 and p=0.024, respectively). The results showed that patient age and a novel biological prognostic marker, podoplanin, are useful for predicting a poor outcome of patients after complete resection of stage IB SqCC of the lung.

・Koop K, Eikmans M, Wehland M, Baelde H, Ijpelaar D, Kreutz R, Kawachi H, Kerjaschki D, de Heer E, Bruijn JA.

Selective Loss of Podoplanin Protein Expression Accompanies Proteinuria and Precedes Alterations in Podocyte Morphology in a Spontaneous Proteinuric Rat Model.

Am J Pathol. 2008 Jul 3. [Epub ahead of print]
(PubMed)

To evaluate changes during the development of proteinuria, podocyte morphology and protein expression were evaluated in spontaneously proteinuric, Dahl salt-sensitive (Dahl SS) rats. Dahl SS rats on a low-salt diet were compared with spontaneously hypertensive rats (SHR) at age 2, 4, 6, 8, and 10 weeks. Blood pressure, urinary protein excretion, urinary albumin excretion, and podocyte morphology were evaluated. In addition, the expression of 11 podocyte-related proteins was determined by analyzing protein and mRNA levels. In Dahl SS rats, proteinuria became evident around week 5, increasing thereafter. SHR rats remained non-proteinuric. Dahl SS rats showed widespread foot process effacement at 10 weeks. At

・抗Podoplanin抗体には、D2-40、AngioBioから発売されているクローン名不明の抗ポドプラニン抗体、また最近中和抗体として注目されているNZ-1などいくつか知られている。しかし、抗体の反応性に関してまだ混乱が多く、以下の論文にてこれらの抗体について検討を行った。

Ogasawara S, Kaneko MK, Price JE, Kato Y.

Characterization of anti-podoplanin monoclonal antibodies: critical epitopes for neutralizing the interaction between podoplanin and CLEC-2.

Hybridoma, 27(4), 259-267, 2008

Podoplanin (Aggrus) is a mucin-type sialoglycoprotein that is known as a useful marker for lymphatic endothelium and tumor-initiating cells (TICs). Interaction between podoplanin and C-type lectin-like receptor-2 (CLEC-2) is reported to be critical for podoplanin-induced platelet aggregation and cancer metastasis. Recently, several anti-human podoplanin antibodies have been established; however, anti-podoplanin antibodies have not been well characterized. Here, five anti-podoplanin antibodies were investigated; NZ-1, D2-40, AB3, 18H5, and a rabbit polyclonal antibody using ELISA, Western-blot, and flow cytometry with synthesized podoplanin peptides and deletion mutants of recombinant podoplanin. The epitope of NZ-1 is platelet aggregation-stimulating (PLAG) domain-2/3; the epitope of D2-40, AB3, and 18H5 is PLAG1/2. The epitopes of D2-40 and AB3 are quite similar, although 18H5 is different from D2-40 and AB3. Using flow cytometric analysis, NZ-1 partially inhibited the interaction between podoplanin and CLEC-2, although other antibodies did not. In conclusion, the most frequently used two anti-podoplanin antibodies, D2-40 and AB3, have the same characters, although many studies have reported the difference of D2-40 and AB3. NZ-1 neutralizes the interaction between podoplanin and CLEC-2, which can lead to the development of therapeutic antibodies against podoplanin-dependent cancer metastasis.

・Raica M., Ribatti D., Mogoanta L., Cimpean A.M., Ioanovici S.

Podoplanin expression in advanced-stage gastric carcinoma and prognostic value of lymphatic microvessel density.

Neoplasma. 2008;55(5):455-60
(PubMed)

＜コメント＞抗ポドプラニン抗体（クローン18H5）を使って胃癌の染色を行っている。浸潤性の高い4症例の胃癌でポドプラニンが染色されたと報告しているが、細胞膜ではなく細胞質のみが染まっているようである。膜蛋白であるポドプラニンの発現は主に細胞膜に見られるため、細胞質のみに発現しているという染色結果はnon-specificの可能性が高い。よって、今回の胃癌に発現しているという結果に関しては慎重に対処する必要がある。

In gastric cancer, lymph node metastasis is a major prognostic factor. Tumor lymphangiogenesis promotes metastasis in experimental models, but in human tumors data about the presence and clinical significance of lymphatic vessels in the tumor area are controversial. We investigated 70 patients with advanced-stage gastric carcinoma and the pathological examination showed 40 cases with intestinal subtype and 30 cases with diffuse subtype. Forty three from 70 cases had regional lymph node metastasis. Additional slides were stained with an antibody against podoplanin, and lymphatic microvessel density (LMVD) was evaluated in the tumoral and peritumoral areas. Lymphatic vessels were identified in tumor area in all cases and LMVD was higher in the peritumoral than in the tumor area. Podoplanin-positive vessels in tumor area were usually small, with narrow lumen. A significant correlation was found between LMVD and stage of the tumor (p<0.002) and lymph node metastasis (p<0.031), but not with the pathological subtype and grade of the tumor. We found tumor cells in the lumen of lymphatic vessels in 11 cases, whereas tumor cells expressing podoplanin were found in 4 cases of less differentiated diffuse subtype gastric carcinoma. In conclusion, our results suggest that LMVD predicts tumor stage and lymph node metastasis, and podoplanin-positive tumor cells select a subgroup of tumors with high potential of invasion and metastasis. Key words: gastric cancer, podoplanin, lymphatic microvessel density (LMVD), lymphangiogenesis, prognosis.

・Durchdewald M, Guinea-Viniegra J, Haag D, Riehl A, Lichter P, Hahn M, Wagner EF, Angel P, Hess J.

Podoplanin is a novel fos target gene in skin carcinogenesis.

Cancer Res. 2008 Sep 1;68(17):6877-83.

Expression and function of the oncogenic transcription factor activator protein (AP-1; mainly composed of Jun and Fos proteins) is required for neoplastic transformation of keratinocytes in vitro and tumor promotion as well as malignant progression in vivo. Here, we describe the identification of 372 differentially expressed genes comparing skin tumor samples of K5-SOS-F transgenic mice (Fos(f/f) SOS(+)) with samples derived from animals with a specific deletion of c-Fos in keratinocytes (Fos(Deltaep) SOS(+)). Fos-dependent transcription of selected genes was confirmed by quantitative real-time PCR analysis using tumor samples and mouse back skin treated with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). One of the most differentially expressed genes encodes the small mucin-like glycoprotein Podoplanin (Pdpn), whose expression correlates with malignant progression in mouse tumor model systems and human cancer. We found Pdpn and Fos expression in chemically induced mouse skin tumors, and detailed analysis of the Pdpn gene promoter revealed impaired activity in Fos-deficient mouse embryonic fibroblasts, which could be restored by ectopic Fos expression. Direct Fos protein binding to the Pdpn promoter was shown by chromatin immunoprecipitation and a TPA-induced complex at a TPA-responsive element-like motif in the proximal promoter was identified by electrophoretic mobility shift assays. In summary, we could define a Fos-dependent genetic program in a well-established model of skin tumors. Systematic analysis of these novel target genes will guide us in elucidating the molecular mechanisms of AP-1-regulated pathways that are critically implicated in neoplastic transformation and/or malignant progression.

・Fu J, Gerhardt H, McDaniel JM, Xia B, Liu X, Ivanciu L, Ny A, Hermans K, Silasi-Mansat R, McGee S, Nye E, Ju T, Ramirez MI, Carmeliet P, Cummings RD, Lupu F, Xia L.

Endothelial cell O-glycan deficiency causes blood/lymphatic misconnections and consequent fatty liver disease in mice.

J Clin Invest. 2008 Oct 16; [Epub ahead of print].

Mucin-type O-glycans (O-glycans) are highly expressed in vascular ECs. However, it is not known whether they are important for vascular development. To investigate the roles of EC O-glycans, we generated mice lacking T-synthase, a glycosyltransferase encoded by the gene C1galt1 that is critical for the biosynthesis of core 1-derived O-glycans, in ECs and hematopoietic cells (termed here EHC T-syn(-/-) mice). EHC T-syn(-/-) mice exhibited embryonic and neonatal lethality associated with disorganized and blood-filled lymphatic vessels. Bone marrow transplantation and EC C1galt1 transgene rescue demonstrated that lymphangiogenesis specifically requires EC O-glycans, and intestinal lymphatic microvessels in EHC T-syn(-/-) mice expressed a mosaic of blood and lymphatic EC markers. The level of O-glycoprotein podoplanin was significantly reduced in EHC T-syn(-/-) lymphatics, and podoplanin-deficient mice developed blood-filled lymphatics resembling EHC T-syn(-/-) defects. In addition, postnatal inactivation of C1galt1 caused blood/lymphatic vessel misconnections that were similar to the vascular defects in the EHC T-syn(-/-) mice. One consequence of eliminating T-synthase in ECs and hematopoietic cells was that the EHC T-syn(-/-) pups developed fatty liver disease, because of direct chylomicron deposition via misconnected portal vein and intestinal lymphatic systems. Our studies therefore demonstrate that EC O-glycans control the separation of blood and lymphatic vessels during embryonic and postnatal development, in part by regulating podoplanin expression.

・Marsee DK, Pinkus GS, Hornick JL.

Podoplanin (D2-40) is a Highly Effective Marker of Follicular Dendritic Cells.

Appl Immunohistochem Mol Morphol. 2008 Oct 3. [Epub ahead of print]
(PubMed)

The monoclonal antibody D2-40 recognizes the membrane protein podoplanin, which is an established marker for germ cell tumors, mesotheliomas, and other tumor types and is also expressed in a variety of normal cells including follicular dendritic cells (FDCs). To determine whether podoplanin represents an effective FDC marker for pathologic lymph nodes, we compared immunohistochemical studies (sensitivity, staining patterns, and intensity of staining) for podoplanin (D2-40) with those of the traditional FDC markers CD21, CD35, and clusterin. Paraffin sections of 26 lymph nodes were analyzed, including 4 cases of nodular lymphocyte-predominant Hodgkin lymphoma, 4 angioimmunoblastic T-cell lymphoma, 8 follicular lymphoma (including 3 cases with a component of diffuse large B-cell lymphoma), 5 hyaline-vascular Castleman disease, and 5 reactive lymph nodes with follicular hyperplasia. In all cases, qualitatively and quantitatively podoplanin represented a highly effective marker for detection of FDCs, with staining intensity equal to or greater than that observed for other FDC markers. This study demonstrates that podoplanin is an excellent marker for FDCs and adds to its growing list of diagnostic applications.

・Tsuruo T, Fujita N.

Platelet aggregation in the formation of tumor metastasis.

Proc Jpn Acad Ser B Phys Biol Sci. , 2008;84(6):189-98. (PDF)

Metastasis is the major cause of death from cancer, yet the optimal strategy against it remains uncertain. The pathogenesis of hematogenous metastasis is dynamic and consists of the following steps: 1) detachment of tumor cells from the primary site, 2) invasion into the host's blood vessels, 3) migration in the host's blood stream, 4) transport along the circulation, 5) arrest in or adhesion to the capillary in a distant organ, 6) extravasation, and 7) proliferation within the foreign tissues. A key to successful hematogenous metastasis is tumor survival in the bloodstream because most circulating tumor cells are rapidly destroyed by the shear forces or are attacked by the immune system. Less than 0.01% of these cells result in metastasis. Tumor cell-induced platelet aggregation has been reported to facilitate hematogenous metastasis by increasing the arrest of tumor cell emboli in the microcirculation. Platelet aggregation is also believed to protect tumor cells from immunological assault in the circulation. We have identified Aggrus as a platelet-aggregating factor expressed on a number of human cancers. Because hematogenous metastasis is reduced when neutralizing antibodies or eliminating carbohydrates attenuates Aggrus function, Aggrus's main contribution to hematogenous metastasis of Aggrus-expressing cells, then, is by promoting platelet aggregation. Aggrus could serve as an ideal target for drug development to block metastasis.

・本ホームページのhit数が2万を突破。
(2万hit)

・Kalof AN, Cooper K.

D2-40 immunohistochemistry--so far!

Adv Anat Pathol. 2009 Jan;16(1):62-42008.
(PubMed)

D2-40 is a commercially available monoclonal antibody directed against human podoplanin, a transmembrane mucoprotein that is expressed in lymphatic endothelial cells. Since its introduction, D2-40 immunoexpression has been described in a variety of lymphovascular neoplasms including lymphangioma, Kaposi sarcoma, and hemangioendothelioma, as well as nonvascular neoplasms such as epithelioid mesothelioma, seminoma, and hemangioblastoma. More recently, D2-40 immunoexpression has been reported in primary adrenal cortical tumors, schwannomas, and adnexal tumors of the skin. This brief review provides an update on the ever-expanding proposed applications of D2-40 immunohistochemistry in surgical pathology.

・Mahtab EA, Vicente-Steijn R, Hahurij ND, Jongbloed MR, Wisse LJ, Deruiter MC, Uhrin P, Zaujec J, Binder BR, Schalij MJ, Poelmann RE, Gittenberger-De Groot AC.

Podoplanin deficient mice show a rhoa-related hypoplasia of the sinus venosus myocardium including the sinoatrial node.

Dev Dyn. 2008 Dec 18;238(1):183-193.
(PubMed)

We investigated the role of podoplanin in development of the sinus venosus myocardium comprising the sinoatrial node, dorsal atrial wall, and primary atrial septum as well as the myocardium of the cardinal and pulmonary veins. We analyzed podoplanin wild-type and knockout mouse embryos between embryonic day 9.5-15.5 using immunohistochemical marker podoplanin; sinoatrial-node marker HCN4; myocardial markers MLC-2a, Nkx2.5, as well as Cx43; coelomic marker WT-1; and epithelial-to-mesenchymal transformation markers E-cadherin and RhoA. Three-dimensional reconstructions were made and myocardial morphometry was performed. Podoplanin mutants showed hypoplasia of the sinoatrial node, primary atrial septum, and dorsal atrial wall. Myocardium lining the wall of the cardinal and pulmonary veins was thin and perforated. Impaired myocardial formation is correlated with abnormal epithelial-to-mesenchymal transformation of the coelomic epithelium due to up-regulated E-cadherin and down-regulated RhoA, which are controlled by podoplanin. Our results demonstrate an important role for podoplanin in development of sinus venosus myocardium. Developmental Dynamics 238:183-193, 2009. (c) 2008 Wiley-Liss, Inc.