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Anoxia, wound healing, VL30 elements, and the molecular basis of malignant conversion
1Institute for Molecular Genetics, Baylor College of Medicine, Houston, TX 77030-3498.
Abstract:
Although VL30 retrotransposable elements have been associated with certain cancers for nearly twenty years, because of their expression in rodent malignancies and recombination into murine sarcoma viruses, their causative role, if any, in cancer has been uncertain and enigmatic. Recent findings suggest loss of normal transcriptional control of specific VL30 element expression may make a critical contribution to tumor progression at a step associated with malignant conversion, by bringing into play a cellular program normally involved in wound healing. This program, the fibroblast anoxic response system, includes an adaptation to glycolytic metabolism, secretion of metalloproteinases, and activation of an endonuclease. While appropriate for facilitating debris removal during wound healing, loss of control of this program in a cell which has already progressed to the benign neoplastic state has the potential to simultaneously produce the invasiveness and genomic instability characteristic of malignancy. Examination of tumors and tumor derived cell lines has confirmed that key aspects of this system are in fact activated in cancer.
Insights
Loss of control over VL30 retrotransposable elements reactivates a wound healing program, contributing to cancer progression. This cellular program, the fibroblast anoxic response system, drives invasiveness and genomic instability in malignant cells.
Area of Science:
- Molecular Biology
- Oncology
- Genetics
Background:
- VL30 retrotransposable elements have been linked to cancers for two decades.
- Their precise role in cancer development has remained unclear.
- Expression in rodent malignancies and viral recombination highlighted their potential involvement.
Purpose of the Study:
- To investigate the role of VL30 elements in cancer progression.
- To explore the link between VL30 expression and cellular programs.
- To understand how dysregulated VL30s contribute to malignancy.
Main Methods:
- Analysis of tumor and tumor-derived cell lines.
- Examination of gene expression related to cellular programs.
- Assessing the activation of specific molecular pathways.
Main Results:
- Loss of transcriptional control of VL30 elements is implicated in tumor progression.
- A wound healing program, the fibroblast anoxic response system, is activated.
- This system involves glycolytic metabolism, metalloproteinase secretion, and endonuclease activation.
Conclusions:
- Dysregulated VL30 expression can trigger a wound healing program in neoplastic cells.
- This aberrant activation contributes to cancer invasiveness and genomic instability.
- Key components of the fibroblast anoxic response system are indeed active in cancers.