Many types of cancer are caused by gene mutations in the signaling pathways that control cell growth, such as the hedgehog signaling pathway. A new study from the Karolinska Institutet now surprisingly shows that in colon cancer hedgehog signaling has a protective function.
Mutations that lead to the activation of hedgehog signaling are the cause of almost all cases of basal cell carcinoma (a common form of skin cancer) and certain types of brain tumors.
Previous studies have indicated that hedgehog signaling is also important in other types of cancer, such as colon cancer -- one of the commonest types of cancer in Sweden.
The research team at the Department of Biosciences and Nutrition at Karolinska Institutet's campus in Huddinge, led by Marco Gerling and Rune Toftgård (pictured), has been working alongside researchers in Holland looking at the possibility of influencing cell growth in colon cancer by altering hedgehog signaling.
In view of the fact that tumors consist of different types of cells apart from the cancer cells themselves, the researchers used various databases to analyze gene expression in colon cancer. Although the team was not able to find any activation of the signaling pathway in the cancer cells, it was able to confirm earlier observations that it is only the hedgehog ligand, the protein needed to launch the signaling process that is produced by the cancer cells. In contrast, the hedgehog signaling pathway and expression of its target genes are specifically activated in the surrounding cells of the connective tissue.
To investigate the importance of the hedgehog signaling from cancer cells to connective tissue cells, the researchers used a mouse model in which the signaling pathway could be switched on specifically in the connective tissue cells. When mice were treated with substances that induce colon cancer, the mice with activated hedgehog signaling in the connective tissues developed significantly fewer tumors than those with a normal hedgehog function. When the team then did the opposite -- inhibiting hedgehog signaling in different mouse models -- the mice developed more tumors. The researchers were able to show that the connective tissue cells with activated hedgehog signaling change their gene expression and send a signal back to the tumor cells, inhibiting the development and growth of tumors.
"The results show that non-cancerous cells in tumors have a great capacity to influence how tumors develop," says Marco Gerling, one of the researchers. "In the long term we hope to be able to provide a detailed explanation of how the activation of hedgehog signaling in the cells surrounding the tumor can prevent the growth of tumors and to use this knowledge to develop new types of treatment that can restrain the development of cancer."
The research was funded through support from organizations such as the Swedish Cancer Society, the Swedish Research Council, the German Research Foundation, and the Ruth and Richard Julin Foundation.
Illustration: Rune Toftgård led the study. Photo: Erik Cronberg.
Karolinska Institutet News Release (08/08/16)
Science Daily (08/08/16)
Abstract (Nature Communications; 2016, 7: 12321.)