Entosis is a biological process where a living cell is actively engulfed by another, creating a “cell-in-cell” structure. This phenomenon is an invasion of one cell into a neighbor. Initially observed in epithelial cells, which line the surfaces of body cavities and organs, this process represents a unique interaction between cells. The internalized cell is initially alive and can even divide within its host.
The Mechanism of Entotic Engulfment
The engulfment process of entosis is an active mechanism driven by the invading cell. It begins when adjacent epithelial cells establish connections known as adherens junctions. These junctions link the internal skeletons of neighboring cells and are a prerequisite for internalization. The invading cell then generates internal contractile forces to push into the host cell, which deforms and envelops the invader.
This invasion is powered by the invading cell’s cytoskeleton, a network of protein filaments for cell shape and movement. The interaction of actin and myosin proteins, orchestrated by a signaling pathway involving Rho-GTPase and ROCK, creates the force for one cell to push into another. The host cell is comparatively passive, allowing the contractile invading cell to penetrate its membrane. The result is the complete internalization of the invader within a membrane-bound compartment called an entotic vacuole.
Triggers and Conditions for Entosis
A primary trigger for entosis is the detachment of epithelial cells from their underlying structural support, the extracellular matrix. This loss of anchorage, a condition known as anoikis, can initiate the entotic process as cells seek to re-establish connections. Without their normal mooring, cells can begin to invade their neighbors.
Entosis can also be initiated by other cellular conditions. For example, the process can be triggered during aberrant cell division, or mitosis. If a cell undergoes morphological changes during mitosis, such as excessive rounding, it becomes susceptible to being engulfed. Variations in cell stiffness and intercellular competition are also factors, where a mechanically stronger cell can invade a softer neighbor.
Cellular Fates Following Entosis
Once a cell is internalized, several outcomes are possible. The most common fate for the engulfed cell is death, which is distinct from the programmed cell death known as apoptosis. The host cell actively kills the internalized cell by using its lysosomes, which are organelles containing digestive enzymes, to break down the captive cell in a process involving autophagy proteins.
While death is the most common outcome, some internalized cells experience different fates. A small fraction can survive temporarily and may even divide inside the host cell. In rare cases, an engulfed cell might escape from its host. For the host cell, engulfing a neighbor can provide nutrients from the digested cell, but it can also lead to genomic instability if the invader’s DNA is incorporated into the host.
Biological Significance of Entosis
The biological role of entosis is complex and has dual functions, particularly in cancer. It can act as a tumor suppression mechanism by eliminating tumor cells that have detached from a primary tumor mass. By engulfing and destroying these potentially metastatic cells, entosis prevents them from spreading. This provides a non-apoptotic pathway to eliminate cancerous cells resistant to other death signals.
Conversely, entosis may also contribute to tumor progression. The process can lead to changes in chromosome number, a condition called aneuploidy, which is a hallmark of many cancers. This occurs when the host cell acquires genetic material from the cell it consumed. Furthermore, the ability of cancer cells to consume their neighbors can provide them with nutrients, allowing them to survive in the harsh, nutrient-poor environment of a tumor. This suggests entosis could be a mechanism that selects for more aggressive and resilient cancer cells.