A caspase-6 and anti-HER2 antibody chimeric tumor-targeted proapoptotic molecule decreased metastasis of human osteosarcoma.
Human growth factor receptor-2 (HER2), overexpressed as a result of gene amplification, is detected in 20-40% of patients with breast, ovarian, endometrial, gastric, bladder, prostate, or lung cancers, correlated to metastasis of many tumors, and considered to be a poor prognostic indicator for these tumors. However, the data was controversial for HER2 overexpression and the prognosis of osteosarcoma, which is the most common primary malignant bone tumor, presents a therapeutic challenge in medical oncology due to its metastasis and poor response to current treatments. Previously, we reported that the immunocasp-6 gene fused by a HER2-specific single-chain antibody with domain II of Pseudomonas exotoxin A (PEA) and the 5' end of the truncated active caspase-6 could selectively suppress the HER2-positive tumor growth. In this study, we extend its application. We first confirmed the higher HER2 expression on the surface of metastatic osteosarcoma SOSP-9607(E10) cells, which then be proved specifically addicted to immunocasp-6-induced cells killing in vitro. Thereafter, the efficacy of immunocasp-6 was tested in an osteosarcoma lung metastasis mouse model using intramuscular (i.m.) injections of liposome-encapsulated vectors. Our results showed that the expression of the immunocasp-6 gene not only significantly prolonged animal's survival, but also greatly inhibited tumor metastasis. Thereby, our strategy suggests an alternative approach to treating HER2/neu-positive osteosarcoma.
Wang
Li-Feng
LF
State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, China.
Zhou
Yong
Y
Xu
Yan-Ming
YM
Qiu
Xiu-Chun
XC
Zhou
Ben-Gen
BG
Wang
Fang
F
Long
Hua
H
Chen
Xiang
X
Yang
Tong-Tao
TT
Ma
Bao-An
BA
Fan
Qing-Yu
QY
Yang
An-Gang
AG
D000293:Adolescent; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D001859:Bone Neoplasms / Q000473:pathology*; D053178:Caspase 6 / Q000235:genetics; D045744:Cell Line, Tumor / Q000637:transplantation; D005813:Genes, Synthetic; D015316:Genetic Therapy; D006801:Humans; D000922:Immunotoxins / Q000235:genetics / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008969:Molecular Sequence Data; D012516:Osteosarcoma / Q000473:pathology / Q000517:prevention & control / Q000556:secondary*; D011897:Random Allocation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000627:therapeutic use*; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
D053178:Caspase 6; D000922:Immunotoxins; D018719:Erb-b2 Receptor Tyrosine Kinases; D011993:Recombinant Fusion Proteins; C543058:immunocasp-6; C508053:ERBB2 protein, human