Cancer cells "hijack" the process of spreading healthy cells throughout the body, overturning the pe

As we all know, cancer is a major killer of human health. Although in the past decade or so, there have been many good reports in the field of cancer treatment, and patients have been prolonging their survival, these advances still have not changed people's fear of cancer. One of the main reasons is cancer metastasis, i.e. the spread of cancer cells from the primary tumor to other organs in the body.

Cancer, as a malignant disorder, may quickly spread through the blood and lymphatic systems. As a result, metastasis kills the majority of cancer patients. Patients' survival rates can be considerably improved if metastasis can be prevented. However, developing anti-metastatic therapies has been difficult since it is unclear how the metastatic process is activated in a complicated tumorigenic cascade.

Recently, researchers at the University of Cambridge Cancer Institute published a paper in Nature Genetics titled "The NALCN channel regulates metastasis and nonmalignant cell dissemination".

This study discovered that sodium channels govern the discharge of malignant and normal epithelial cells into the circulation as well as their metastasis to distant organs, a process unrelated to tumor development. As a result, metastasis occurs in both cancer and healthy cells. This work fundamentally alters our understanding of cancer metastasis and identifies a new potential target for the therapy of metastatic cancer.

Because metastasis is considered a completely aberrant process limited to malignant tissues, scientists have long focused on identifying genetic mutations as drivers of cancer metastasis.

Researchers discovered Nalcn (Na+ leak channel, non-selective) as a critical regulator of cancer metastasis and non-malignant cell migration in this recent study. NALCN is in charge of maintaining the resting membrane potential's background sodium leak conductance. Regulation can stimulate important tissue activities such as respiration and circadian rhythms; moreover, gain-of-function mutations in NALCN have been linked to neurological diseases. Scientists are constantly learning about the role of NALCN in non-excitable tissues.

Nonsynonymous mutations in NALCN were enriched in gastric, colorectal, lung, prostate, and head and neck cancers among the 10022 human malignancies in the Cancer Genome Atlas. These tumors also included deletion, nonsense, and shift mutations at rates comparable to those found in TP53 in human malignancies. This indicates that NALCN may act as a tumor suppressor.

To investigate how the loss of NALCN function affects cancer development and progression in solid tissues, researchers bred mice carrying the conditional NALCN allele and induced tumors in their small intestine, liver, lung, salivary gland, prostate, uterus, skin, and stomach. The same number of wild-type healthy mice served as controls.

Experimental results showed that deletion of NALCN from mice with gastric, intestinal, or pancreatic adenocarcinomas did not alter tumor incidence, but significantly increased the number of circulating tumor cells (CTCs) and metastases. Treatment of these mice with NALCN channel inhibitors similarly increased CTCs and metastases.

When NALCN was removed from healthy mice, it caused the same amount of epithelial cells to be lost in the circulation as in tumor-bearing animals. These cells migrate to distant organs and develop into normal structures such as lung epithelium, glomeruli, and renal tubules. Healthy pancreatic cells, for example, were transported to the kidneys and transformed into healthy kidney cells. This suggests that NALCN is responsible for regulating the shedding of malignant and normal epithelial cells into the bloodstream and their translocation to distant organs, where the metastasized cells subsequently form metastatic cancer or normal tissue, respectively.

This study revolutionizes the current view of cancer metastasis by showing that NALCN can regulate cell migration in solid tissues independently of cancer and by distinguishing this process from tumorigenesis. These observations have profound implications for understanding epithelial cell trafficking in health and disease and for identifying new targets for antimetastatic therapy.

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