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Role of insulin-like growth factor binding protein-4 in prevention of colon cancer
Rajaraman Durai1, Shi Y Yang, Alexander M Seifalian
1Academic Division of Surgical and Interventional Sciences, University College London, London, UK. a.seifalian@ucl.ac.uk.
Background:
Insulin-like growth factors (IGFs) are important for the proliferation of cancer cells. One of their binding proteins, known as insulin-like growth factor binding protein -4 (IGFBP-4) is well known for its inhibitory action on IGFs in vitro. We assessed the effect of IGFBP-4 in prevention of development of colon cancer in vivo.
Methods:
Nude mice were subcutaneously inoculated with HT-29 colon cancer cells and they were also simultaneously injected either gene construct containing mammalian expression vector pcDNA3 with or without IGFBP-4 gene or phosphate buffered saline. The effect was assessed 4 weeks later by evaluating the tumours for mitosis, necrosis, apoptosis, and expressions of IGFBP-4, Bcl-2 and Bax proteins.
Results:
The results showed that the IGFBP-4 gene therapy did not prevent the tumour establishment but it increased the tumour apoptosis which was associated with an increase in Bcl-2 and Bax expressions. The IGFBP-4 protein was low in tumours which received IGFBP-4 gene construct which may be due to a feed back mechanism of IGFBP-4 upon its own cells.
Conclusion:
IGFBP-4 gene therapy in the form localised gene transfer did not prevent colon cancer initiation and establishment but it resulted in increased apoptosis and Bax protein expression and a decrease in tumour cellular mitosis.
Insights
Insulin-like growth factor binding protein-4 (IGFBP-4) gene therapy did not prevent colon cancer in mice. However, it increased tumor cell death (apoptosis) and decreased tumor cell division (mitosis).
Area of Science:
- Oncology
- Molecular Biology
- Gene Therapy
Background:
- Insulin-like growth factors (IGFs) promote cancer cell proliferation.
- Insulin-like growth factor binding protein-4 (IGFBP-4) inhibits IGF activity in vitro.
- The role of IGFBP-4 in colon cancer development in vivo requires investigation.
Purpose of the Study:
- To evaluate the effect of IGFBP-4 gene therapy on colon cancer development in vivo.
- To assess the impact of IGFBP-4 on tumor apoptosis, necrosis, and cellular mitosis.
- To analyze the expression of IGFBP-4, Bcl-2, and Bax proteins in tumors.
Main Methods:
- Nude mice were inoculated with HT-29 colon cancer cells.
- Mice received gene constructs with or without IGFBP-4 or phosphate-buffered saline.
- Tumor analysis included assessment of mitosis, necrosis, apoptosis, and protein expression (IGFBP-4, Bcl-2, Bax) after 4 weeks.
Main Results:
- IGFBP-4 gene therapy did not prevent tumor establishment.
- Increased tumor apoptosis was observed, associated with elevated Bcl-2 and Bax expression.
- Low IGFBP-4 protein levels in treated tumors suggest a feedback mechanism.
Conclusions:
- Localised IGFBP-4 gene transfer did not prevent colon cancer initiation.
- IGFBP-4 gene therapy increased apoptosis and Bax protein expression.
- A decrease in tumor cellular mitosis was observed following IGFBP-4 gene therapy.
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