Studies have shown that tumor cells prepare the recipient organs to form metastases by releasing exosomes.
November 30, 2015 Source: Bio Valley
Window._bd_share_config={ "common":{ "bdSnsKey":{ },"bdText":"","bdMini":"2","bdMiniList":false,"bdPic":"","bdStyle":" 0","bdSize":"16"},"share":{ }};with(document)0[(getElementsByTagName('head')[0]||body).appendChild(createElement('script')) .src='http://bdimg.share.baidu.com/static/api/js/share.js?v=89860593.js?cdnversion='+~(-new Date()/36e5)];The spread of cancer cells from the origin to the distant organs through the blood is the leading cause of cancer-related death. This process is not random; instead, some types of cancer cells go through a series of molecular procedures that give priority to finding specific organs and nesting there. This search for destination involves the interaction of cancer cells (sometimes referred to as "seeds") that evade the primary tumor from the microenvironment (or "soil" at the target organ. Hoshino et al.'s study found that seeds can be used to affect the "soil" through extracellular vesicles called exosomes before they arrive, thus preparing for tumor metastasis.
There is growing evidence that there is a series of systemic responses before the primary tumor metastasis that even contribute to the metastasis of cancer. These reactions may include complex changes in the body's blood vessels, blood clotting, and inflammation—for example, cancer-related changes include changes in cell types, soluble proteins, and exosomes in the blood.
Hoshino et al. define exosomes as small, transporting proteins, lipids, and nucleic acids from one cell to another, and can travel along the blood to distant extracellular vesicles. Exosomes have attracted much attention in the field of cancer research because some extracellular vesicles carry oncogenes, promoting cancer formation and disease progression.
External vesicles, including exosomes, played an important role in several key events in the formation of the metastatic microenvironment and preparation for metastasis, which researchers have studied for several years. For example, in a mouse model of melanoma, the interaction between the exosomes and the capillary wall causes changes in vascular permeability, allowing tumor cells to escape from the blood vessels and enter a new site. In addition, exosomes can transfer the oncogene MET receptor protein to circulating bone marrow cells, thereby altering their behavior and preparing for cancer metastasis. In the pancreatic cancer model, exosomes in the blood transfer the metastasis suppressor protein to the Kupffer cell of the liver, triggering a cascade of events that promote the formation of the metastatic microenvironment.
Although these results indicate that exosomes promote tumor metastasis, studies on whether exosomes and how to participate in organ-specific metastasis of tumors are scarce. To study this problem, Hoshino et al. asked whether cancer cells that preferentially metastasize to the lungs, liver, brain or bone might interact with these organs through exosomes before metastasis. The experimental results are exactly the same. Exosomes of cancer cells are injected into mice, and these exosomes are retained in organs where cancer cells tend to metastasize. In addition, these organ-specific exosomes interact with different cell types. For example, exosomes that target the lung will adhere to endothelial cells in the lung, while exosomes that target the liver will enter Kupffer immune cells.
Hoshino et al. injected exosomes of cancer cells into the same cell line, demonstrating that exosomes promote organ-specific metastasis of tumors. Then they found an interesting phenomenon - the exosomes of breast cancer cells that are transferred to the lungs can redirect another type of tumor cells that normally metastasize to the bones to the lungs. This finding further confirms that the metastatic characteristics of tumor cells are not autonomous but are influenced by external factors.
Hoshino et al. provide several clues as to how exosomes affect organ-specific metastasis. They found that exosomes targeting different organs possess different cell adhesion receptor proteins, the integrins on the cell surface. Different types of exosomes tend to enter organs that have a large number of ligands corresponding to their surface integrins. For example, αVβ5 integrin directs exosomes to the liver, while α6β4 directs to the lungs (Fig. 1). In addition, inhibition of expression of extracellular bodies or expression of integrins can inhibit cancer metastasis. Finally, when Hoshino exosomes invade the target organ, they cause the synthesis of S100 protein, which promotes inflammation and cell migration, and activates the Src protein, which lays the foundation for the metastasis of cancer cells.
a, exosomes are released from the cells of the primary tumor, enter the bloodstream, and transport proteins, lipids, and nucleic acids to cells at the distal end of the body.
Hoshino et al. found that the integrins on the surface of exosomes secreted by different tumor cells are different. The type of integrin determines the type of cell to which the exosomes adhere. For example, integrin α6β4 and α6β1 play key roles in lung metastasis, while integrin αvβ5 plays a key role in liver metastasis. b, the contents of the exosomes cause changes in the cells of the target organ, thus preparing for cancer metastasis. Exosomes direct their cancer cells into specific organs, promoting organ-specific metastasis and proliferation of tumor cells.
These important findings expand our understanding of the specific transfer of tumor organs. However, how to translate this understanding into clinical means requires more research. Hoshino et al. demonstrated that integrin expression predicts metastasis and points to the potential of exosomes integrin for cancer diagnosis. Their data also suggest that integrin inhibitors may reduce the metastasis of cancer in specific organs. However, in many cases, advanced cancer spreads to multiple organs, limiting the application prospects of organ-specific metastasis.
It should be noted that the molecular pathways of tumor metastasis (whether exosomal dependent and independent) may be very numerous. Therefore, they may be affected by many related factors: activation of different pathways in tumor cells, emergence of a specific molecular subtype in tumors, and intervention therapy. For example, the incidence of brain metastases between breast cancer subtypes is different, and the oncogenic protein ERBB2 type breast cancer is more likely to metastasize to the brain even after effective treatment with ERBB2 inhibitors. What scientists don't know is whether ERBB2 inhibitor treatment affects and how it affects the release of organ-prone exosomes. They have great interest in the research of this subject. Similarly, inflammation, coagulopathy, and other cancer-related physiological changes may be related to organ orientation mechanisms in exosomes, so these factors must be fully considered when analyzing the metastatic pathway. Therefore, the mechanisms by which exosomes are directed to specific organs and affect the "soil" in different types of cancer require more research.
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