| RRC ID |
77028
|
| 著者 |
Hiramatsu K, Serada S, Enomoto T, Takahashi Y, Nakagawa S, Nojima S, Morimoto A, Matsuzaki S, Yokoyama T, Takahashi T, Fujimoto M, Takemori H, Ueda Y, Yoshino K, Morii E, Kimura T, Naka T.
|
| タイトル |
LSR Antibody Therapy Inhibits Ovarian Epithelial Tumor Growth by Inhibiting Lipid Uptake.
|
| ジャーナル |
Cancer Res
|
| Abstract |
Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy, but it still lacks effective treatment options. In this study, we utilized proteomic technology to identify lipolysis-stimulated lipoprotein receptor (LSR) as a new tumor antigen of EOC. Immunohistochemical analysis of EOC tissues in conjunction with survival analysis of EOC patients showed that high expression of LSR is associated with poor prognosis. High LSR expression also occurred in tumor metastases including to the lymph node and omentum. To evaluate the possible benefits of blocking this antigen in EOC, we raised a new monoclonal antibody (mAb) to human LSR (hLSR). In mouse xenograft models of hLSR+ EOC (cell lines or patient-derived tumors), we found that administration of anti-hLSR mAb inhibited tumor growth in a manner independent of both antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. Mechanistic investigations showed that hLSR expression increased incorporation of very-low-density lipoprotein (VLDL) into EOC cells and that anti-hLSR mAb inhibited lipid uptake in vitro and in vivo Moreover, VLDL promoted cell proliferation in hLSR-positive EOC cells in vitro, and this effect was inhibited by anti-hLSR mAb. While the anti-hLSR mAb studied cross reacted with the mouse antigen, we observed no adverse effects on normal organs and lipid metabolism in murine hosts. Our findings suggest that hLSR plays a key functional role in EOC development and that this antigen can be therapeutically targeted by specific mAb to improve EOC treatment.Significance: These findings offer preclinical evidence of the therapeutic efficacy of a novel targeted antibody therapy against deadly epithelial ovarian cancers. Cancer Res; 78(2); 516-27. ©2017 AACR.
|
| 巻・号 |
78(2)
|
| ページ |
516-527
|
| 公開日 |
2018-1-15
|
| DOI |
10.1158/0008-5472.CAN-17-0910
|
| PII |
0008-5472.CAN-17-0910
|
| PMID |
29187404
|
| MeSH |
Adult
Aged
Animals
Antibodies, Monoclonal / pharmacology*
Antibody-Dependent Cell Cytotoxicity
Apoptosis
Biomarkers, Tumor / metabolism*
Carcinoma, Ovarian Epithelial
Case-Control Studies
Cell Proliferation
Female
Follow-Up Studies
Humans
Lipids / pharmacokinetics*
Male
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Nude
Middle Aged
Neoplasm Recurrence, Local / immunology
Neoplasm Recurrence, Local / metabolism
Neoplasm Recurrence, Local / pathology
Neoplasm Recurrence, Local / therapy*
Neoplasms, Glandular and Epithelial / immunology
Neoplasms, Glandular and Epithelial / metabolism
Neoplasms, Glandular and Epithelial / pathology
Neoplasms, Glandular and Epithelial / therapy*
Ovarian Neoplasms / immunology
Ovarian Neoplasms / metabolism
Ovarian Neoplasms / pathology
Ovarian Neoplasms / therapy*
Prognosis
Proteomics
Receptors, Lipoprotein / immunology*
Receptors, Lipoprotein / metabolism
Survival Rate
Tissue Distribution
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
|
| IF |
9.727
|
| リソース情報 |
| ヒト・動物細胞 |
JHOS-4(RCB1678) |
