The selective metastasis of cancer cells to specific organs is a complex process that is influenced not only by anatomical factors but also by biological and organ-specific microenvironmental factors. The pre-metastatic niche refers to soluble factors and extracellular vesicles (EVs) produced by cells at the primary tumor site, which can modify the microenvironment of distant organs to accommodate migrating cancer cells and promote their growth. In addition, disseminated tumor cells (DTCs) can enter a dormant state in the circulation and in the new tissue environment, evade immune surveillance, and interact with the tissue microenvironment to awaken from dormancy. Finally, metastatic colonization requires multiple biological processes. These processes rely on the intrinsic properties of cancer cells and the permissive tumor microenvironment provided by cells in the target organ.
During colorectal cancer liver metastasis, both the intrinsic properties of colorectal cancer cells and the interactions of molecules and cells in the microenvironment affect metastasis. Once colorectal cancer cells successfully enter the liver microenvironment, they interact with cell adhesion molecules on liver sinusoidal endothelial cells, leading to the encapsulation and adhesion of disseminated tumor cells (DTCs).
When a large number of tumor cells invade the liver, the anti-tumor function of Kupffer cells (KCs) may be suppressed. Colorectal cancer cells may interact with KCs to stimulate the secretion of growth factors such as hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF), and this stimulation promotes tumor cell proliferation and angiogenesis. Hepatocytes also play an important role in liver metastasis. Hepatocytes can also release a variety of growth factors, all of which promote tumor growth, motility, and invasion. However, the mechanism by which hepatocytes promote tumor metastasis is not fully understood.
AFDN is located on chromosomes and is a major component of adherens junctions (AJs), which form adherens junctions between adjacent epithelial cells. As a scaffold protein of adherens junctions, AFDN can recruit cadherin or connexins and interact with actin to promote the formation of adherens junctions. The role of AFDN in tumors was first reported in acute myeloid leukemia. In acute myeloid leukemia, fusion with lysine-specific methyltransferase 2A (MLL) leads to changes in AFDN subcellular localization and activation of the Ras signaling pathway, promoting the progression of acute myeloid leukemia and leading to poor prognosis. However, AFDN mainly plays a tumor suppressor role in various solid tumors.
Loss or downregulation of AFDN expression is associated with poor prognosis in colorectal cancer, osteosarcoma, endometrial cancer, breast cancer, and pancreatic cancer. In pancreatic cancer, loss of AFDN not only disrupts adhesion and tight junctions, but also upregulates the expression of Snail, promoting epithelial-mesenchymal transition (EMT) and metastasis. AFDN also maintains adherens junctions and inhibits tumor cell migration and invasion by interacting with cystic fibrosis transmembrane conductance regulator (CFTR) in CRC. However, the biological functions and molecular mechanisms of AFDN in the liver of colorectal cancer patients are still unclear.
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Recently, researchers from Zhejiang University School of Medicine in China published an article titled "AFDN deficiency promotes liver tropism of metastatic colorectal cancer" in the journal Cancer Res. The study showed that AFDN deficiency can promote liver metastasis of colorectal cancer, providing a new perspective and understanding for studying the mechanism of liver metastasis of colorectal cancer.
Liver metastasis is the main cause of morbidity and mortality in patients with colorectal cancer. A better understanding of the biological mechanisms of liver tropism and metastasis of colorectal cancer will help to identify better prevention and treatment strategies. In this study, the researchers performed a genome-wide CRISPR functional loss screening in a mouse colorectal cancer model and found that AFDN deficiency is a driver of liver metastasis. Elevated AFDN expression is associated with prolonged survival in colorectal cancer patients. Colorectal cancer cells lacking AFDN preferentially metastasize to the liver rather than the lungs. AFDN loss at the primary site of colorectal cancer cells promotes cancer cell migration and invasion by disrupting tight intercellular junctions.
Figure 1. Schematic of the screening process for liver metastasis-related genes in colorectal cancer using the CRISPR/Cas9 library. (Liao S, et al., 2024)
In addition, through the JAK-STAT signaling pathway, CXCR4 expression is increased in AFDN-deficient colorectal cancer cells, thereby reducing the motility of AFDN-deficient colorectal cancer cells and promoting their colonization in the liver.
In summary, the role of AFDN in cancer progression is very complex. AFDN deficiency reduces intercellular TJs, thereby promoting the migration and invasion of colorectal cancer cells. AFDN deficiency also inhibits their movement in the liver, ultimately leading to the formation of liver metastases. However, the molecular mechanisms underlying the specificity and liver tropism of AFDN deficiency in colorectal cancer metastasis remain to be elucidated.
Reference
Liao S, et al. AFDN deficiency promotes liver tropism of metastatic colorectal cancer. Cancer Research, 2024.