GD1α‐replica peptides functionally mimic GD1α, an adhesion molecule of metastatic tumor cells, and suppress the tumor metastasis

Ishikawa, Dai; Kikkawa, Hironori; Ogino, Kōichi; Hirabayashi, Yoshio; Oku, Naoto; Taki, Takao

doi:10.1016/s0014-5793(98)01511-7

Cited by 51 publications

(30 citation statements)

References 21 publications

(23 reference statements)

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“…6) Phage-displayed random peptide libraries are useful to obtain specific peptides interacting with target molecules such as receptors and adhesion molecules. 11,12) The present data indicate that LFPLH may inhibit angiogenesis in a manner similar to WRP-containing peptides, the antiangiogenic activity of which was clarified in our previous study.…”

Section: Fig 3 Effect Of Lfplh and Its Shuffled Peptide On Huvec MIsupporting

confidence: 72%

Isolation of a Novel Peptide Homing to Tumor-Derived Neovasculature That Suppresses Tumor Growth.

Asai

Fukatsu

Kuromi

et al. 2002

Biological & Pharmaceutical Bulletin

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Tumor angiogenesis is prerequisite for solid tumor growth, since tumor cells require oxygen and nutrients from the blood. Thus angiogenesis inhibitors are a new category of drugs for inducing tumor dormancy. Antiangiogenic agents are thought to be free of severe side effects, effective for any type of solid tumor, 1,2) and to suppress hematogenous metastases.3) We speculate that specific ligands against molecules on angiogenic endothelial cells have the potential to suppress angiogenesis, since angiogenic vasculature has different properties from preexisting systemic vasculature. 4,5) Furthermore, such ligands may provide vascular targeting probes for tumor angiogenic vasculature. We recently isolated peptides specific for tumor angiogenic vasculature by using a phagedisplayed peptide library.6,7) Briefly, we injected a phage-displayed peptide library into dorsal air sac (DAS)-bearing angiogenic model mice, 8) which enabled us to isolate phage clones specific for only angiogenic sites but not for tumor cells. Then the peptide sequences of the isolated phage clones were analyzed. Among them, ASSSYPLIHWRPW-AR, DRWRPALPVVLFPLH, and PRPGAPLAGSWPGTS presented phages highly accumulated in the tumor tissues of two different tumor cell types. 6) One of the isolated peptides, ASSSYPLIHWRPWAR, suppressed the migration of vascular endothelial growth factor (VEGF)-stimulated human umbilical vein endothelial cells (HUVECs) in vitro, and dendoric ASSSYPLIHWRPWAR-peptide [KK 2 K 4 (ASSSYPLI-HWRPWAR) 8 ] suppressed the formation of new blood vessels in DAS model mice.7) Thus we determined the epitope sequence of ASSSYPLIHWRPWAR-peptide using fragment peptides such as ASSYPLIH and IHWRPWAR. IHWRP-WAR showed tumor growth suppression but ASSYPLIH did not. In such way, we determined the epitope sequence for the ASSSYPLIHWRPWAR-peptide to be WRP. 7)In the present study, we similarly determined the epitope sequence for DRWRPALPVVLFPLH. Interestingly, not only DRWRPALP, which has the WRP sequence, but also PV-VLFPLH showed tumor growth suppression in vivo. Thus further study was performed focused on PVVLFPLH to obtain a novel peptide epitope causing tumor dormancy through inhibition of angiogenesis. MATERIALS AND METHODSPeptide Synthesis Peptides were synthesized using Rink amide resin and a peptide synthesizer ACT357 (Advanced ChemTech, Louisville, KY, U.S.A.) as described previously. 6)Tumor Implantation and Therapeutic Experiment The therapeutic experiment was performed according to the procedure described previously. 7) Meth A sarcoma cells were grown in BALB/c male mice (Japan SLC Inc. Shizuoka, Japan) under an appropriate schedule, and were diluted with saline to obtain a 5ϫ10 6 cells/ml suspension. Then 0.2 ml of the suspension was injected subcutaneously into the posterior flank of 5-week-old BALB/c male mice. Synthetic 15-mer peptides and fragment peptides (20 mg/kg/day) were injected subcutaneously into a site adjacent to the tumor of tumorbearing mice every day starting on day 1 until day 10 after tumor implantation. Inject...

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Section: Fig 3 Effect Of Lfplh and Its Shuffled Peptide On Huvec MIsupporting

confidence: 72%

Isolation of a Novel Peptide Homing to Tumor-Derived Neovasculature That Suppresses Tumor Growth.

Asai

Fukatsu

Kuromi

et al. 2002

Biological & Pharmaceutical Bulletin

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“…In addition to fucosylated carbohydrate antigens, sialylated complex carbohydrate structures, such as GD1␣, are closely related to metastasis (40). Not only these terminal carbohydrate structures, but internal structures, particularly those forming polylactosamines, are closely related to cancer malignancy (41,42).…”

Section: Discussionmentioning

confidence: 99%

Identification of mRNA splicing factors as the endothelial receptor for carbohydrate-dependent lung colonization of cancer cells

Hatakeyama

Sato

Nakayama

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Cell surfaces of epithelial cancer are covered by complex carbohydrates, whose structures function in malignancy and metastasis. However, the mechanism underlying carbohydrate-dependent cancer metastasis has not been defined. Previously, we identified a carbohydrate-mimicry peptide designated I-peptide, which inhibits carbohydrate-dependent lung colonization of sialyl Lewis X-expressing B16-FTIII-M cells in E/P-selectin doubly-deficient mice. We hypothesized that lung endothelial cells express an unknown carbohydrate receptor, designated as I-peptide receptor (IPR), responsible for lung colonization of B16-FTIII-M cells. Here, we visualized IPR by in vivo biotinylation, which revealed that the major IPR is a group of 35-kDa proteins. IPR proteins isolated by I-peptide affinity chromatography were identified by proteomics as Ser/Arg-rich alternative pre-mRNA splicing factors or Sfrs1, Sfrs2, Sfrs5, and Sfrs7 gene products. annexin ͉ galectin ͉ metastasis ͉ selectin ͉ vasculature T he apical cell surface of epithelia is covered by numerous carbohydrates attached to membrane proteins and lipids. When epithelial cells are transformed, the structure of these carbohydrates changes (1). Many investigators have suggested a correlation between cancer-associated carbohydrate antigens and poor patient prognosis, including metastasis (2-8). Despite extensive structural analysis and clinical observations using monoclonal antibodies against cancer-associated carbohydrate antigens, mechanisms underlying carbohydrate-dependent cancer metastasis through the circulation remain elusive. Because E-selectin is expressed on the inflammatory endothelial cell surface and binds to cancer-associated carbohydrate antigens such as sialyl Lewis A (sLeA) and sialyl Lewis X (sLeX), E-selectin provides a mechanism for sLeA and/or sLeX antigenexpressing cancer cells to be metastasized through the hematogenous route (4-6). Involvement of P-selectin and L-selectin in cancer metastasis has been also described (7,8). However, substantial clinical data indicate the existence of selectin-independent but carbohydrate-dependent cancer metastasis (6, 10, 11).In our previous studies, we screened a peptide-displaying phage library using a monoclonal anti-Lewis A antibody (clone 7LE) and identified a short peptide IELLQAR, designated I-peptide (12-14). When I-peptide was injected intravenously into a mouse, it bound to a specific subset of lung capillary endothelial cells but not to blood vessels of other organs including the liver (12). I-peptide administration inhibited carbohydrate-dependent lung colonization of fucosyltransferase-3-transfected sialyl Lewis X antigenpositive B16 (B16-FTIII-M) cells (15) in wild-type mice (12) and in E-and P-selectin doubly-deficient mutant mice (13), suggesting that the lung endothelial surface expresses unknown carbohydratebinding receptor(s) enabling colonization of B16-FTIII-M cells. We designated this presumptive receptor I-peptide receptor (IPR) (13).In this study, we isolated IPR candidate proteins by I-peptideaff...

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“…In general, biopanning of a phage-displayed peptide library is performed in vitro: The desired short peptide-expressing phages are isolated by their ability to bind to speci®c antibodies (Ishikawa et al, 1998;Takikawa et al, 2000), proteins (Gho et al, 1997;Healy et al, 1995;Koivunen et al, 1993), or glycoconjugates (Martens et al, 1995). On the other hand, Pasqualini and Ruoslahti (1996) developed a strategy of in vivo biopanning: The phage-displayed peptide library is directly injected into the bloodstream of animals to isolate speci®c peptideexpressing phage clones homing to the desired organ.…”

Section: Introductionmentioning

confidence: 99%

Anti-neovascular therapy using novel peptides homing to angiogenic vessels

et al. 2002

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Cancer chemotherapy targeted to angiogenic vessels is expected to cause indirect tumor regression through the damage of the neovasculature without the induction of drug resistance. To develop a tool for neovasculaturespeci®c drug delivery, we isolated novel peptides homing to angiogenic vessels formed by a dorsal air sac method from a phage-displayed peptide library. Three distinct phage clones that markedly accumulated in murine tumor xenografts presented PRPGAPLAGSWPGTS-, DRWRPALPVVLFPLH-or ASSSYPLIHWRPWARpeptide respectively. After the determination of the epitope sequences of these peptides, we modi®ed liposomes with epitope penta-peptides. Liposome modi®ed with APRPG-peptide showed high accumulation in murine tumor xenografts, and APRPG-modi®ed liposome encapsulating adriamycin eectively suppressed experimental tumor growth. Finally, speci®c binding of APRPG-modi®ed liposome to human umbilical endothelial cells, and that of PRP-containing peptide to angiogenic vessels in human tumors, i.e., islet cell tumor and glioblastoma, were demonstrated. The present study indicates the usefulness of APRPG-peptide as a tool for anti-neovascular therapy, a novel modality of cancer treatment.

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GD1α‐replica peptides functionally mimic GD1α, an adhesion molecule of metastatic tumor cells, and suppress the tumor metastasis

Cited by 51 publications

References 21 publications

Isolation of a Novel Peptide Homing to Tumor-Derived Neovasculature That Suppresses Tumor Growth.

Isolation of a Novel Peptide Homing to Tumor-Derived Neovasculature That Suppresses Tumor Growth.

Identification of mRNA splicing factors as the endothelial receptor for carbohydrate-dependent lung colonization of cancer cells

Anti-neovascular therapy using novel peptides homing to angiogenic vessels

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