A Fas Ligand (FasL)-fused humanized antibody against tumor-Associated glycoprotein 72 selectively exhibits the cytotoxic effect against oral cancer cells with a low FasL/Fas ratio

Ming Hsien Chien, Wei Min Chang, Wei Jiunn Lee, Yu Chan Chang, Tsung Ching Lai, Derek V. Chan, Rahul Sharma, Yuan Feng Lin, Michael Hsiao

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Altered expression of the Fas ligand (FasL)/Fas ratio exhibits a direct impact on the prognosis of cancer patients, and its impairment in cancer cells may lead to apoptosis resistance. Thus, the development of effective therapies targeting the FasL/Fas system may play an important role in the fight against cancer. In this study, we evaluated whether a fusion protein (hcc49scFv- FasL) comprising of the cytotoxicity domain of the FasL fused to a humanized antibody (CC49) against tumor-Associated glycoprotein 72, which is expressed on oral squamous cell carcinoma (OSCC), can selectively kill OSCC cells with different FasL/Fas ratios. In clinical samples, the significantly low FasL and high Fas transcripts were observed in tumors compared with normal tissues. A lower FasL/Fas ratio was correlated with a worse prognosis of OSCC patients and higher proliferative and invasive abilities of OSCC cells. The hcc49scFv-FasL showed a selective cytotoxic effect on OSCC cells (Cal-27 and SAS) but not on normal oral keratinocytes cells (HOK) through apoptosis induction. Moreover, SAS cells harboring a lower FasL/Fas ratio than Cal-27 were more sensitive to the cytotoxic effect of hcc49scFv-FasL. Unlike wild-Type FasL, hcc49scFv-FasL was not cleaved by matrix metalloproteinases and did not induce nonapoptotic signaling in SAS cells. In vivo, we found that hcc49scFv-FasL drastically reduced the formation of lymphnode metastasis and decreased primary tumor growth in SAS orthotopic and subcutaneous xenograft tumor models. Collectively, our data indicate that a tumor-Targeting antibody fused to the FasL can be a powerful tool for OSCC treatment, especially in populations with a low FasL/Fas ratio.

Original languageEnglish
Pages (from-to)1102-1113
Number of pages12
JournalMolecular Cancer Therapeutics
Volume16
Issue number6
DOIs
Publication statusPublished - Jun 1 2017

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Antibodies, Monoclonal, Humanized
Fas Ligand Protein
Mouth Neoplasms
Squamous Cell Carcinoma
Neoplasms
tumor-associated antigen 72
Apoptosis
Neoplasm Antibodies
Matrix Metalloproteinases
Keratinocytes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

A Fas Ligand (FasL)-fused humanized antibody against tumor-Associated glycoprotein 72 selectively exhibits the cytotoxic effect against oral cancer cells with a low FasL/Fas ratio. / Chien, Ming Hsien; Chang, Wei Min; Lee, Wei Jiunn; Chang, Yu Chan; Lai, Tsung Ching; Chan, Derek V.; Sharma, Rahul; Lin, Yuan Feng; Hsiao, Michael.

In: Molecular Cancer Therapeutics, Vol. 16, No. 6, 01.06.2017, p. 1102-1113.

Research output: Contribution to journalArticle

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abstract = "Altered expression of the Fas ligand (FasL)/Fas ratio exhibits a direct impact on the prognosis of cancer patients, and its impairment in cancer cells may lead to apoptosis resistance. Thus, the development of effective therapies targeting the FasL/Fas system may play an important role in the fight against cancer. In this study, we evaluated whether a fusion protein (hcc49scFv- FasL) comprising of the cytotoxicity domain of the FasL fused to a humanized antibody (CC49) against tumor-Associated glycoprotein 72, which is expressed on oral squamous cell carcinoma (OSCC), can selectively kill OSCC cells with different FasL/Fas ratios. In clinical samples, the significantly low FasL and high Fas transcripts were observed in tumors compared with normal tissues. A lower FasL/Fas ratio was correlated with a worse prognosis of OSCC patients and higher proliferative and invasive abilities of OSCC cells. The hcc49scFv-FasL showed a selective cytotoxic effect on OSCC cells (Cal-27 and SAS) but not on normal oral keratinocytes cells (HOK) through apoptosis induction. Moreover, SAS cells harboring a lower FasL/Fas ratio than Cal-27 were more sensitive to the cytotoxic effect of hcc49scFv-FasL. Unlike wild-Type FasL, hcc49scFv-FasL was not cleaved by matrix metalloproteinases and did not induce nonapoptotic signaling in SAS cells. In vivo, we found that hcc49scFv-FasL drastically reduced the formation of lymphnode metastasis and decreased primary tumor growth in SAS orthotopic and subcutaneous xenograft tumor models. Collectively, our data indicate that a tumor-Targeting antibody fused to the FasL can be a powerful tool for OSCC treatment, especially in populations with a low FasL/Fas ratio.",
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AU - Chien, Ming Hsien

AU - Chang, Wei Min

AU - Lee, Wei Jiunn

AU - Chang, Yu Chan

AU - Lai, Tsung Ching

AU - Chan, Derek V.

AU - Sharma, Rahul

AU - Lin, Yuan Feng

AU - Hsiao, Michael

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