Potential therapeutic targets to inhibit colorectal cancer progression

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Australian researchers and colleagues from Nagoya University, Japan, have revealed that colorectal cancer tissues contain at least two types of fibroblasts (a type of cells found in connective tissue), namely, cancer-promoting fibroblasts and cancer-restraining fibroblasts, and that the balance between them is largely involved in the progression of colorectal cancer.

Their findings, recently published in the journal Gastroenterology, suggest that artificially altering the balance between the two types of cells could curb the spread of colorectal cancer tumours, which may become an effective strategy for preventing cancer progression.

Cancer tissues comprise both cancer cells and non-malignant cells such as fibroblasts.

Previous studies have suggested that the proliferation of fibroblasts is largely involved in the progression of colorectal cancer, the most common cancer in Japan.

Fibroblasts within cancer tissues, called cancer-associated fibroblasts (CAFs), are considered to be divided into at least two populations: those that promote cancer progression and those that restrain it.

Impeding the function of cancer-promoting CAFs could be a promising method to prevent cancer progression, but a lack of understanding of the mechanism underlying heterogeneity of CAFs has hampered its development.

In normal colon tissues, proteins called bone morphogenetic proteins (BMPs), which are secreted by stromal cells, are known to play a critical role in regulating intestinal homeostasis, whereas in cancerous colon tissues, they are considered to be associated with cancer progression.

In this context, the research team led by Professors Atsushi Enomoto and Masahide Takahashi of the Graduate School of Medicine at Nagoya University in Japan conducted a study to determine how stroma cells lead BMPs to be involved in the progression of colorectal cancer.

The team first analysed comprehensive gene expression profiling data to identify BMP-related genes that are specifically expressed in colorectal CAFs.

Two types of proteins, meflin and gremlin 1, were identified to be encoded by such genes.

Next, to investigate the relevance of these proteins in colorectal cancer progression, Prof. Enomoto and his colleagues, who had previously shown that meflin plays a role in restraining the progression of pancreatic cancer, conducted a study in collaboration with researchers from the University of Adelaide and the South Australian Health and Medical Research Institute, who have conducted studies focusing on the role of gremlin 1 as a BMP inhibitor in the intestine.

The joint research group examined the prognostic significance of the expression of meflin and gremlin 1 in colorectal cancer patients and found that, interestingly, those with a high expression of meflin have a favourable prognosis, whereas those with a high expression of gremlin 1 have an unfavourable prognosis.

In addition, experiments using a mouse model revealed that the proliferation of colorectal cancer cells can be suppressed through administration of a gremlin 1-neutralising antibody or over expression of meflin.

Regarding the role of BMP signalling mediated by stromal gremlin 1 and meflin in colorectal cancer, Prof. Enomoto explains, “We hypothesise that CAFs mediated by gremlin 1 promote cancer progression by decreasing BMP signalling, whereas CAFs mediated by meflin restrain the growth of the cancer by reinforcing BMP signalling.”

Therefore, intensifying stromal BMP signalling, either by using a gremlin 1-neutralising antibody or by over expressing meflin, could be an attractive therapeutic strategy to treat colorectal cancer.


Source: NAGOYA UNIVERSITY

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The ONA Editor curates oncology news, views and reviews from Australia and around the world for our readers. In aggregated content, original sources will be acknowledged in the article footer.

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