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Deleted in Colorectal Cancer (DCC) pathfinding: axon guidance gene finally turned tumor suppressor
1Department of Medical and Molecular Genetics, Indiana University School of Medicine, South Bend, IN 46617, USA. mscheel@nd.edu
Abstract:
Loss of heterozygosity (LOH) at human chromosome 18q, which includes the gene Deleted in Colorectal Cancer (DCC), has been linked to colorectal and many other human cancers. DCC encodes the receptor for the axon guidance molecule Netrin (Net) and functions during neural development in a variety of organisms. However, since its discovery in the 1990s, the status of DCC as a tumor suppressor has been debated, primarily due to a lack of support for this hypothesis in animal models. A recent study from our laboratory capitalized on the genetic tractability of Drosophila melanogaster to demonstrate that this gene functions as an invasive tumor suppressor, thereby providing the first direct link between DCC loss and metastatic phenotypes in an animal model for cancer. Two subsequent studies from other laboratories have demonstrated that DCC suppresses tumor progression and metastasis in murine colorectal and mammary tumor models. Combined, these findings have prompted the rebirth of DCC as a tumor suppressor and highlighted the need for continued analysis of DCC function in animal models for human cancer.
Insights
Loss of heterozygosity at chromosome 18q, involving the Deleted in Colorectal Cancer (DCC) gene, is linked to cancers. DCC acts as an invasive tumor suppressor, confirmed in fruit fly and mouse models, supporting its role in cancer progression.
Area of Science:
- Oncology
- Developmental Biology
- Genetics
Background:
- Loss of heterozygosity (LOH) at human chromosome 18q, including the Deleted in Colorectal Cancer (DCC) gene, is associated with various cancers.
- DCC, a receptor for Netrin, plays a role in neural development, but its function as a tumor suppressor has been debated due to limited animal model evidence.
Purpose of the Study:
- To investigate the role of DCC as a tumor suppressor in a cancer model.
- To provide direct evidence linking DCC loss to metastatic phenotypes in an animal model.
Main Methods:
- Utilized the genetic tractability of Drosophila melanogaster (fruit fly) to study DCC function.
- Reviewed subsequent studies in murine colorectal and mammary tumor models.
Main Results:
- Demonstrated that DCC functions as an invasive tumor suppressor in a Drosophila model.
- Provided the first direct link between DCC loss and metastatic phenotypes in an animal model.
- Subsequent studies confirmed DCC's suppression of tumor progression and metastasis in mouse models.
Conclusions:
- The findings support the rebirth of DCC as a tumor suppressor.
- Highlight the importance of continued analysis of DCC function in animal models for human cancer.
- DCC loss is directly linked to cancer metastasis.
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