As we all know, cancer is the number one "killer" of human health. Although good news in the field of cancer treatment has been frequent over the past decade and patients have continued to prolong their survival, these progress has not changed the situation of "discussing cancer". One of the most important reasons is cancer metastasis, where cancer cells spread from the primary tumor to other organs of the body.
As a malignant disease, cancer is easily metastasized through blood and lymph and other channels. Therefore, most cancer patients end up dying from metastasis. If metastasis can be blocked, the survival rate of patients can be significantly improved. However, to date, development of anti-metastasis therapy has been difficult, as how metastasis processes are triggered in a complex tumorigenesis cascade remains elusive.
Recently, in a new study published in "Nature Genetics", a research team from the Cancer Institute of the University of Cambridge in the UK found that the sodium ion channel regulates the shedding of malignant and normal epithelial cells into the blood and transfer to distant organs. This process is independent of tumor formation. Therefore, metastasis occurs not only in cancer cells, but also in healthy cells. This study has completely changed the way we think about cancer metastasis.
Because metastasis is considered to be a completely abnormal process and is limited to malignant tissues, scientists have long focused on identifying gene mutations as a driver of cancer metastasis.
In this new study, researchers identified sodium leakage channel nonselective protein (NALCN) as a key regulator of cancer metastasis and nonmalignant cell migration. NALCN is responsible for maintaining background sodium leakage conduction of resting membrane potential. Regulation of key functions that can excitate tissues, such as respiratory and circadian rhythms; and, mutations in the acquisition of NALCN are associated with neurological diseases. However, little is still known about the role of NALCN in non-exciting tissues.
In 10022 human cancers in the cancer genome map, non-synonymous mutations of NALCN are enriched in gastric cancer , colorectal cancer, lung cancer, prostate cancer , and head and neck cancer. These cancers also contain deletion, nonsense, and frameshift mutations, with frequencies very similar to those observed in TP53. This suggests that NALCN may be a tumor suppressor.
To study how NALCN function loss affects the occurrence and progress of cancer in solid tissues, the researchers cultivated mice carrying conditioned NALCN alleles and induced tumors in their small intestine, liver, lung, salivary glands, , prostate, uterine , skin and stomach. The same number of wild-type healthy mice were used as control groups.
experimental results show that deletion of NALCN from gastric, intestinal or pancreatic adenocarcinoma in mice did not change the incidence of tumors, but significantly increased the number of circulating tumor cells (CTCs) and metastatic tumors. Treating these mice with gadolinium (a NALCN channel blocker) also increased CTCh and metastasis.
When NALCN was removed from healthy mice, its epithelial cells were caused to fall out into the blood at the same level as those of tumor-bearing mice. These cells are transferred to distant organs and form normal structures, including the lung epithelium, glomerulus and tubules, . For example, healthy cells from pancreas are migrated to the kidneys, where they become healthy kidney cells.
This shows that NALCN is responsible for regulating the shedding of malignant and normal epithelial cells into the blood and the transport to distant organs, and the metastasized cells then form metastatic cancer or normal tissue, respectively.
In summary, this study revolutionizes current perceptions of cancer metastasis, suggesting that NALCN can independently regulate cell migration in solid tissues and distinguish this process from tumorigenesis. These observations have profound implications for understanding the transport of epithelial cells in health and disease and for identifying new targets for anti-metastatic therapy.
Paper link:
https://doi.org/10.1038/s41588-022-01182-0
Source: China Biotechnology Network
Orchestration: Dai Wei Xia Bingbing
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