Colorectal Cancers Raise Defensive Barrier in Response to Chemotherapy

A side-by-side comparison of colorectal cancer cells before (left) and after (right) treatment with fluorouracil and irinotecan. The expression of mucins is shown in green.

Drugs which are commonly-used as the first line of treatment for colorectal cancer cause the tumour cells to oversecrete proteins known as mucins, according to a new study published today in the journal eLife. The proteins alter the mucous layer, forming a physical barrier that prevents drugs from reaching their intended target.

Using different techniques involving genetic manipulation and the use of chemical inhibitors, the research team were able to experimentally regulate mucin secretion in cancer cell lines and patient-derived organoids, paving the way for the development of future treatments that can be used alongside chemotherapy to target drug-resistant forms of colorectal cancer. The experiments also revealed potential new biomarkers for the prognosis of the disease.

The researchers studied mucins, which are heavy, sugar-coated proteins that are secreted by specialised cells in the linings of the eye, nose, airway and the digestive tract, including the colon. On average, humans secrete up to a litre of mucins per day. Mucins have gel-forming properties that mix with other biological matter to form mucous, a thick liquid that acts as a lubricant, preventing tissues from becoming dehydrated and also forming a barrier to protect cells from pathogens and other external factors.

Colorectal cancer occurs when tumours develop in the colon or rectum. Adenocarcinomas are the most common type of colorectal cancer, often growing from the cells that constitute the mucous lining of the tissue. The researchers studied whether the overexpression of mucins could create a barrier for drugs reaching the tumour cells. Experiments with fluorouracil and irinotecan, two drugs given in combination as the first-line treatment for colorectal cancer, revealed that cancer cells respond to the treatment by secreting copious amounts of mucin.

“15-20% of colorectal cancers are linked to the overproduction of mucin. In some of these cases, this is a problem because it will block drugs from reaching their intended target. What we were surprised to find is that chemotherapy itself triggers mucin secretion, potentially trapping patients in a vicious cycle requiring increasingly higher doses. This can be stopped if chemotherapy is combined with treatments that inhibit mucin secretion,” says ICREA Research Professor Vivek MalhotraCoordinator of the Cell & Developmental Biology Programme at the CRG and author of the study.

The researchers studied different ways of blocking mucin secretion to make tumour cells more sensitive to the drugs. They first attempted to genetically manipulate levels of the protein KChIP3, previously shown by Dr. Malhotra’s research group to regulate mucin secretion. They found that colorectal cancer cells depleted of KChIP3 were four times more drug-resistant compared to cells with normal levels of KChIP3. In contrast, cells with higher than normal levels of KChIP3 were ten times more sensitive to chemotherapeutic drugs.

According to Dr. Lluís EspinosaCoordinator of the Molecular Mechanisms of Cancer and Stemness at Hospital del Mar Medical Research Institute (IMIM), researcher at CIBER Cancer (CIBERONC) and co-author of the study“the downside of using KChIP3 as a therapeutic target is that it requires the use of gene therapy, a technology that is still in its developmental stages and also very expensive to use.”

The authors of the study then assessed KChIP3’s potential as a biomarker for the prognosis of colorectal cancer. By studying publicly available datasets following the progression of patients with colorectal cancer patient, they found that high levels of KChIP3 indicated a longer period of time for disease-free survival, the length of time after primary treatment for a cancer ends that the patient survives without any signs or symptoms of that cancer.

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