Loss of motility-related protein 1 (MRP1/CD9) and integrin ?3 expression in endometrial cancers

Miyamoto, Shingo; Maruyama, Akiko; Okugawa, Kaoru; Akazawa, Kohei; Baba, Hideo; Maehara, Yoshihiko; Mekada, Eisuke

doi:10.1002/1097-0142(20010801)92:3<542::aid-cncr1353>3.0.co;2-8

Cited by 30 publications

(17 citation statements)

References 17 publications

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“…Several studies showed an increased expression of ␣3 integrin associated with higher metastatic ability (13,14). Using immunohistochemistry, Miyamoto (15) showed that reduced ␣3-integrin expression in endometrial cancers correlates with histological grade and metastasis. Adachi et al (16) obtained similar results in lung adenocarcinoma.…”

Section: Discussionmentioning

confidence: 99%

Differential Gene Expression in Metastasizing Cells Shed from Kidney Tumors

et al. 2004

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We developed a novel orthotopic mouse tumor model of renal cell carcinoma to collect and characterize cells spontaneously shed from SN12C (renal cell carcinoma) and SN12L1 (high metastatic variant of SN12C) tumors grown in kidneys of severe combined immunodeficient mice. Viability of the shed cell population was greater for SN12L1 tumors (25%) compared with SN12C tumors (11%, P < 0.05). Gene array analysis of 23 genes involved in metastasis showed that CD44, ␣3 integrin, and caveolin were down-regulated in the shed tumor cells compared with their primary counterparts, and blocking ␣3 integrin or CD44 function inhibited attachment and migration of both cell lines. These results suggest that cohesion of the cells within the primary tumor mediated by CD44 and ␣3 integrins hinders metastasis and that shedding is a passive process not necessarily mediated by cell migration in these tumors. Furthermore, resistance to apoptosis may enhance metastasis in the higher metastatic tumor.

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Section: Discussionmentioning

confidence: 99%

Differential Gene Expression in Metastasizing Cells Shed from Kidney Tumors

et al. 2004

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“…Among the molecules involved in cell motility, tetraspanins MRP-1/CD9 and KAI1/CD82 have been identified as suppressors of tumor spread (6,7). The expression of these tetraspanins is observed in almost all normal tissues, and these molecules are believed to mediate migration signals through forming membrane complexes with integrin receptors (8,9). Supporting these observations, numerous previous studies have shown a reduced expression of either MRP-1/CD9 or KAI1/CD82 in various tumors to correlate with the presence of distant metastasis and a poorer prognosis (10)(11)(12)(13).…”

Section: Introductionmentioning

confidence: 99%

Adenoviral Transduction ofMRP-1/CD9andKAI1/CD82Inhibits Lymph Node Metastasis in Orthotopic Lung Cancer Model

et al. 2007

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Conventional therapies still remain less effective for metastasis of lung cancer, thus leading to a poor prognosis for this disorder. Although the processes involved in metastasis have not yet been clearly elucidated, our previous studies have shown that higher expression levels of MRP-1/CD9 and KAI1/ CD82 in cancer cells are significantly correlated with less metastatic potency. To determine whether the gene transfer of these tetraspanins into lung tumor cells may be a useful strategy to regulate metastasis, we adopted an orthotopic lung cancer model produced by the intrapulmonary implantation of Lewis lung carcinoma (LLC) cells and evaluated the metastatic growth in the mediastinal lymph nodes using two different methods of gene delivery as follows: (a) the implantation of LLC cells preinfected with adenovirus encoding either MRP-1/CD9 cDNA, KAI1/CD82 cDNA, or LacZ gene into the mouse lung and (b) the intratracheal administration of these adenoviruses into the mice orthotopically preimplanted with LLC cells. In both cases, we found that the delivery of either MRP-1/CD9 or KAI1/CD82 cDNA dramatically reduced the metastases to the mediastinal lymph nodes in comparison with those of LacZ gene delivery, without affecting the primary tumor growth at the implanted site. These results reemphasize the important role of MRP-1/CD9 and KAI1/CD82 in the suppression of the metastatic process and also show the feasibility of gene therapy when using these tetraspanins for lung cancer to prevent metastasis to the regional lymph nodes. This strategy may therefore be clinically applicable as a prophylactic treatment to suppress the occurrence of lymph node metastasis. [Cancer Res 2007; 67(4):1744-9]

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“…Recently, a tetraspanin family member, CD82/KAI1, believed to be a metastasis suppressor, has been shown to interact with a protein (DARC [Duffy antigen receptor for chemokines]) on endothelial cells and to induce senescence of tumor cells, 44 indicating a role in preventing ectopic dissemination. Another tetraspanin member, CD9, is believed to suppress migration signals by forming membrane complexes with integrin receptors, 4,5,45 and has been identified as a metastasis suppressor. 13,[36][37][38] However, it has not been clearly or concretely elucidated how the motility change acts, or which metastatic step is affected.…”

Section: Discussionmentioning

confidence: 99%

“…3 Numerous previous studies have shown reduced CD9 expression in various cancers, which correlated with the presence of distant metastasis and a poorer prognosis. [4][5][6][7][8][9][10][11] The clinical importance of CD9 in the diagnosis, staging, and prognosis of tumors has been growing. 12 Recently, it was reported that adenoviral transduction of CD9 inhibited lymph node metastasis in an orthotopic lung cancer model.…”

Section: Introductionmentioning

confidence: 99%

Tetraspanin family member CD9 inhibits Aggrus/podoplanin-induced platelet aggregation and suppresses pulmonary metastasis

Nakazawa

Sato

Naito

et al. 2008

Blood

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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 TM2) of CD9. Investigation of the interaction revealed that each CD9 and Aggrus interacted homophilically, and that they colocalized in lowdensity membrane fractions. Deleting TM1 and TM2 attenuated the ability of CD9 to interact homophilically or to localize in low-density membrane fractions. The expression of CD9-wild-type (WT), but not CD9 lacking TM1 and TM2, 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. (Blood. 2008;112:1730-1739) IntroductionFour-pass transmembrane proteins of the tetraspanin family regulate cell migration, fusion, and signaling events by functioning as organizers of a multimolecular membrane complex called the tetraspanin web or tetraspanin-enriched microdomains. 1,2 The CD9 protein is a member of the tetraspanin family and has been identified as a suppressor of cancer spread. 3 Numerous previous studies have shown reduced CD9 expression in various cancers, which correlated with the presence of distant metastasis and a poorer prognosis. [4][5][6][7][8][9][10][11] The clinical importance of CD9 in the diagnosis, staging, and prognosis of tumors has been growing. 12 Recently, it was reported that adenoviral transduction of CD9 inhibited lymph node metastasis in an orthotopic lung cancer model. 13 The investigators evaluated metastatic growth in the mediastinal lymph nodes using gene delivery of CD9. These findings strongly suggest that CD9 plays indispensable roles in malignant tumor progression and shows the feasibility of gene therapy to prevent metastasis. However, we cannot say that the therapeutic application of CD9 is now available. Functions of tetraspanins, to a great extent, may depend on expression patterns of their counterparts or other molecules on the tetraspanin web. Actually, there are reports that overexpression of CD9 does not affect metastatic properties, 14 or that CD9 expression is downregulated at the primary site but reexpressed at the metastatic site. 15 So, the precise mechanisms of the metastasis suppression should be elucidated more clearly.Aggrus/podoplanin, a type-I transmembrane glycoprotein, has been shown to be up-regulated in a number of different cance...

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Loss of motility-related protein 1 (MRP1/CD9) and integrin ?3 expression in endometrial cancers

Cited by 30 publications

References 17 publications

Differential Gene Expression in Metastasizing Cells Shed from Kidney Tumors

Differential Gene Expression in Metastasizing Cells Shed from Kidney Tumors

Adenoviral Transduction ofMRP-1/CD9andKAI1/CD82Inhibits Lymph Node Metastasis in Orthotopic Lung Cancer Model

Tetraspanin family member CD9 inhibits Aggrus/podoplanin-induced platelet aggregation and suppresses pulmonary metastasis

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