Introduction: about one in every 25 people will suffer from colon cancer in their lifetime. Nearly 2 million new cases are diagnosed every year in the world. Chemotherapy is commonly used to treat colon cancer. Although this treatment is initially effective in most cases, many patients relapse after treatment. Scientists have found that tumor stem cells with mex3a protein activity are still in a latent state and thus become resistant to chemotherapy. Due to the effect of the drugs used for this treatment, these cells take a similar embryonic state, and at some time after chemotherapy, when the environment is more favorable, they are reactivated to regenerate all the complexity of the tumor. These are the causes of cancer recurrence after treatment.
Recently, under the leadership of Dr. Eduard Batlle, icrea researcher and director of IRB Barcelona colorectal cancer laboratory, the cause of colon cancer recurrence was revealed. Their research was published in the journal Nature cancer. The title is: "mex3a marks drug tolerance persistent colorectal cancer cells that mediate release after chemotherapy". Some tumor cells are still in a latent state, and after chemotherapy, they are reactivated, leading to recurrence.
https://www.nature.com/articles/s43018-022-00402-0
01 chemotherapy is still irreplaceable
Chemotherapy is one of the most effective methods to treat cancer at present, and it is called the three major treatment methods of cancer together with surgery and radiotherapy. Surgery and radiotherapy belong to local treatment, which is only effective for the tumor at the treatment site. It is difficult to exert effective treatment for the cancer with clinical metastasis. Chemotherapy is a means of systemic treatment. No matter what route of Administration (oral, intravenous and intraluminal), chemotherapy drugs will spread throughout most organs and tissues of the body with blood circulation. Therefore, chemotherapy is the main treatment.
Dr. Batlle explained: "chemotherapy is effective and can kill most tumor cells, but not all. Our findings reveal the identity of a group of durable cells that are resistant to chemotherapy and continue to regenerate tumors after treatment. Our work paves the way for the development of drugs that eliminate these cells, which will make chemotherapy more effective and improve survival.".
02 analysis of organoids and patient samples
This study was mainly conducted using organoids, which are tumor samples from patients (or mouse models of advanced cancer) that can grow in the laboratory and reproduce the complexity of tumors in terms of their three-dimensional structure and the variability of cell types. "Organoids enable us to track the evolution of cells throughout the process and observe their response to chemotherapy," explained Adri á n á lvarez Varela, the first author of the study.
The study also involved the use of a mouse model of colorectal cancer, in which researchers were able to observe and reproduce the behavior of these persistent cells, such as organoids. Finally, the results obtained from organoids and mice were compared with transcriptomic analysis of patient samples.
03 mex3a gene
In addition, Dr. Batlle and his collaborators showed that removing the mex3a gene through genetic engineering technology makes colorectal cancer cells highly sensitive to chemotherapy. In experimental models of this type of cancer, mex3a deficient metastasis was completely eliminated by chemotherapy. Although the function of the mex3a gene is unclear, this finding suggests that drugs targeting it can synergize with chemotherapy and prevent recurrence.
Future laboratory work will focus on analyzing the underlying molecular mechanisms, especially how mex3a protein maintains cancer stem cells in this dormant state. It will also address chemotherapy triggered processes that allow cells to produce a state similar to the embryonic state, which makes it possible for them to regenerate the different cell types present in tumors at the end of treatment.
Reference material:
https://www.nature.com/articles/s43018-022-00402-0
https://medicalxpress.com/news/2022-07-scientists-unravel-key-colon-cancer.html
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