Related Experiment Video
Updated: Aug 9, 2026
An Orthotopic Mouse Model of Anaplastic Thyroid Carcinoma
Published on: April 17, 2013
Antitumor capacity of a dominant-negative RET proto-oncogene mutant in a medullary thyroid carcinoma model
M Drosten1, T Stiewe, B M Pützer
1Center for Cancer Research and Cancer Therapy, Institute of Molecular Biology, University of Essen Medical School, 45122 Essen, Germany.
Abstract:
Gain-of-function mutations in the RET proto-oncogene resulting in a constitutively active receptor tyrosine kinase have been identified as responsible for three subtypes of multiple endocrine neoplasia type 2 (MEN-2) and the development of sporadic medullary and papillary thyroid carcinoma. An important strategy in cancer gene therapy is the inhibition of oncogenic signal transduction by interfering with the molecular mechanisms of activation. In the present study, we tested the therapeutic capacity of an adenovirus expressing a dominant-negative (dn) RET mutant, RET(51).flag, under the control of a synthetic C cell-selective calcitonin promoter (TSE2.CP1) against human medullary thyroid cancer (MTC). Infection of human MTC-derived TT cells with Ad-TSE2.CP1-dn-RET(51).flag resulted in the accumulation of immature RET protein in the endoplasmic reticulum and a strong reduction of oncogenic RET receptor on the cell surface, indicating that RET(51).flag exhibits a dominant-negative effect over endogenous oncogenic protein. Analysis of potential downstream mechanisms associated with the inhibition of oncogenic RET signaling by overexpression of mutant RET(51).flag revealed a significant loss of cell viability in TT cells due to the induction of apoptosis. Finally, we examined the antitumor activity of the dominant-negative RET approach in vivo. Inoculation of Ad-TSE2.CP1- dn-RET(51).flag-expressing MTC cells into nude mice led to complete suppression of tumor growth. Moreover, a single intratumoral injection of Ad-TSE2.CP1-dn-RET(51).flag into established thyroid tumors resulted in prolonged survival of treated mice compared with the controls. Our data suggest that adenoviral delivery of dn-RET(51).flag may be a reliable strategy of effective molecular intervention for RET oncogene-related MTC.
Insights
This study demonstrates that an adenovirus carrying a dominant-negative RET mutant effectively inhibits medullary thyroid cancer growth. This gene therapy approach shows promise for treating RET oncogene-related thyroid cancers.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Gain-of-function mutations in the RET proto-oncogene drive multiple endocrine neoplasia type 2 (MEN-2) and thyroid cancers.
- Targeting oncogenic RET signaling is a key strategy in cancer gene therapy.
Purpose of the Study:
- To evaluate the therapeutic potential of an adenovirus expressing a dominant-negative RET mutant (dn-RET(51).flag) against human medullary thyroid cancer (MTC).
Main Methods:
- Adenovirus expressing dn-RET(51).flag under a calcitonin promoter (Ad-TSE2.CP1-dn-RET(51).flag) was used to infect MTC cells.
- The effect on RET protein localization, cell viability, apoptosis, and tumor growth in vivo was analyzed.
Main Results:
- Infection led to reduced cell surface RET and induced apoptosis in MTC cells.
- In vivo studies showed complete suppression of MTC tumor growth and prolonged survival in mice.
- The dn-RET(51).flag exhibited a dominant-negative effect on endogenous oncogenic RET.
Conclusions:
- Adenoviral delivery of dn-RET(51).flag is a promising strategy for molecular intervention in RET oncogene-related MTC.
- This approach effectively inhibits MTC cell viability and tumor growth, suggesting its therapeutic potential.
Related Concept Videos
02:23Abnormal Proliferation
01:33Cancer-Critical Genes I: Proto-oncogenes
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
01:12Loss of Tumor Suppressor Gene Functions
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
01:05Cancer-Critical Genes II: Tumor Suppressor Genes
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
01:20The Retinoblastoma Gene
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...