The Role of Netrin-1 in Shrinking Tumors and Preventing Cancer Metastasis
Background
Endometrial adenocarcinoma is a type of cancer that develops in the innermost layer of the uterus. It is classed as an ‘adenocarcinoma’ because it is malignant and it originates in epithelial cells. As the tumor develops it can metastasize, which is one of the hallmarks of cancer progression. Metastasis refers to cells breaking off from the tumor and moving to other parts of the body through blood vessels. Cancers that can normally be treated by chemotherapy can become deadly if they metastasize to areas of the body like the brain, lungs or liver.
In order for metastasis of endometrial carcinomas (EC) to occur, the epithelial cells must undergo the epithelial-to-mesenchymal transition (EMT). This is necessary because epithelial cells are stationary within tissues; they can’t detach from their basal lamina (the layer of tissue that the epithelium is anchored to). Mesenchymal cells, on the other hand, can detach, travel to the bloodstream, and make it to other parts of the body. In this study, researchers explored how regulating the expression of a specific protein affected cancer cells’ ability to survive and go through EMT.
Summary
In this study scientists focused on the netrin-1 protein. This secreted glycoprotein is believed to play a role in determining how stem cells migrate during embryonic development so that they can differentiate into a specific cell type. After a baby is fully developed and born, netrin-1 no longer needs to be expressed in any cells, but previous research has shown that it is expressed in some cancer cells.
The researchers decided to study the effects of inhibiting the netrin-1 protein expressed in tumor cells of an EC. They designed an antibody named NP137 that would bind to netrin-1 and cause a conformational change in the protein. When a protein undergoes a conformational change it means that it is changing shape, and this can prevent it from binding to its receptor which in this case is UNC5B.
This article discusses both pre-clinical and clinical tests using NP137 as a netrin-1 inhibitor. In the pre-clinical tests, the scientists tested NP137 on mice with a deleted Pten gene. The Pten gene is a tumor suppressor gene, which means that it codes for a protein that prevents cells from over-proliferating. When the Pten gene is deleted from mice, they form tumors — specifically endometrial carcinomas. Pten-deleted mice treated with the NP137 antibody showed several positive results. They showed tumor shrinkage (meaning increased cancer cell death) and fewer tumor cells had undergone EMT (less chance of metastasis).
In a follow-up experiment, the scientists tested how NP137 would affect a tumor’s sensitivity to chemotherapy. Previous studies have shown that when tumor cells transition from epithelial to mesenchymal, the tumor becomes more resistant to chemotherapy because it’s microenvironment changes. The researchers gave Pten-deleted mice a standard chemotherapeutic called carbotaxol to treat their tumor and then also gave a group of them NP137. The mice treated with carbotaxol and NP137 had a higher survival rate than mice treated with just the chemotherapy drug, showing that inhibiting netrin-1 decreases a tumor’s chemotherapy resistance.
The inhibitor NP137 was also tested in a clinical study. The article discusses one particular case where an elderly woman with endometrial carcinoma that had metastasized to her liver was given NP137 intravenously. She had already received several chemotherapy treatments without much success. After six weeks of treatment with NP137, doctors performed a PET-CT scan on her to see the size of the tumors in her liver and to determine if the NP137 treatment had caused them to shrink. A PET-CT scan shows the areas of the body that are using the most glucose. Cancer cells take up more glucose than normal cells so tumors show up very obviously on PET-CT scans. The scan showed that the patient’s liver tumors had decreased in size after treatment, but she did end up receiving more chemotherapy treatments afterward.
Overall, the designed antibody NP137 shows promise as a treatment for endometrial carcinomas. Its ability to inhibit the protein netrin-1 in cancer cells makes them more susceptible to chemotherapy treatments. Additionally, NP137 was shown to promote cancer cell apoptosis and cause tumor shrinkage in mice, even without the administration of a chemotherapeutic. An NP137 treatment could be a viable option for patients with endometrial cancer in the near future.
