An international team of researchers including scientists at the HSE Faculty of Biology and Biotechnology has identified factors which can increase the aggressiveness of tumours in patients with colorectal cancer. An isoform of CD44 protein has been found to play a pivotal role in the development of metastases. The study findings have been published in Molecular Oncology.
The study was conducted as part of HSE University's Basic Research Programme.
Colorectal cancer is the third most common cancer worldwide. It tends to remain asymptomatic and to be first diagnosed at advanced stages when it responds poorly to treatment. The decisive factor influencing the survival of colorectal cancer patients is the occurrence of distant metastases that affect other organs. The presence of metastases is responsible for more than 90% of colorectal cancer-related deaths.
Tumour cells that have detached from the primary tumour can give rise to metastases, but this occurs only if the detached tumour cells include stem cells. The presence of these cells is signalled by an elevated expression of the CD44 protein: its levels often rise significantly with the progression of cancers. The CD44 protein is characterised by a variety of isoforms, which are distinct forms of the same protein originating from a common gene. Previous studies indicated the presence of CD44 isoforms 3 and 4 in colorectal cancer tumours, yet their role in cancer progression remained contentious.
An international team including researchers from the HSE Faculty of Biology and Biotechnology analysed data from colorectal cancer patients, comparing the expression levels of total CD44 and its individual isoforms. They discovered that patients with higher expression of isoform 3 exhibited a more favourable disease course and better survival rates. Conversely, patients with elevated expression of isoform 4 demonstrated more aggressive tumour behaviour and a higher incidence of metastases.
By analysing patient data, the study authors have discovered that these two isoforms of the same protein regulate identical processes in the body but in opposite directions: isoform 3 facilitates cellular respiration and normal behaviour, whereas isoform 4 triggers hypoxia, fostering a more aggressive behaviour in tumour cells.
In cases where tumour cells lack sufficient oxygen, they emit signals that stimulate an increased formation of microvessels within the tumour. With an increased presence of these microvessels in their vicinity, malignant cells find it easier to enter the bloodstream, spread throughout the body, and reintegrate into tissues in locations distant from the primary tumour. If stem cells detach from the primary tumour, they have the capability to establish a new tumour, ie metastasis occurs. Moreover, hypoxia induces a transformation in the tumour cells themselves, rendering them more aggressive, which seems to play a critical role in cases of colorectal cancer exhibiting a high level of CD44 isoform 4..
The scientists have experimentally confirmed their hypothesis regarding the fatal role of CD44. In the experiment, mice were injected with human colorectal cancer cells in which the expression of CD44 had been suppressed. Despite the formation of a primary tumour, the mice showed improved survival rates. Animals with the ‘switched off’ CD44 gene exhibited significantly fewer metastases in the lungs, liver, and bone marrow compared to the control group of mice injected with cancer cells expressing active CD44.
For the first time, we have found answers to crucial questions: identifying the most perilous CD44 isoform for people with colorectal cancer, understanding the interplay between isoforms 3 and 4, and exploring the consequences of suppressing the expression of this protein. However, there is still much more to uncover. For example, while the transformation of normal tissue into tumour tissue involves an increase in the expression of isoform 3, the tumour’s capability to spread further seems to be determined by isoform 4. Possibly, the course and aggressiveness of colorectal cancer depend on the specific ratio of these two isoforms.
The findings from the study could mark the first step towards an innovative treatment for intestinal cancer: inhibiting CD44 isoform 4 might diminish the likelihood of metastases in patients and substantially decrease mortality rates associated with colorectal cancer.