Cell extrusion, discovered in 2001,
is a process conserved in
epithelial
Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellula ...
from humans to sea sponge
to seamlessly remove unwanted or dying cells while maintaining the integrity of the epithelial barrier.
If cells were to die without extrusion, gaps would be created, compromising the epithelia's function. While cell targeted to die by apoptotic stimuli extrude to prevent gaps from forming,
most cells die as a result of extruding live cells.
To maintain epithelial cell number homeostasis, live cells extrude when they become too crowded.
Function
Cell extrusion enables the removal of less fit and excess cells from the epithelia and endothelia. Apoptotic epithelial cell extrusion was first discovered as a way to prevent gaps when cell die within an epithelial layer.
In vertebrates, most cells extrude out apically into the lumen, however, during fruit fly development, they extrude basally, back into the tissue the epithelia encase where they are engulfed.
During
homeostasis
In biology, homeostasis (British English, British also homoeostasis) Help:IPA/English, (/hɒmɪə(ʊ)ˈsteɪsɪs/) is the state of steady internal, physics, physical, and chemistry, chemical conditions maintained by organism, living systems. Thi ...
, live cell extrusion drives most epithelial cell death when too many cells accumulate. To maintain constant cell numbers, crowding signals some cells to extrude, which then later die through
anoikis Anoikis is a form of programmed cell death that occurs in anchorage-dependent cells when they detach from the surrounding extracellular matrix (ECM). Usually cells stay close to the tissue to which they belong since the communication between proxima ...
, or death due to lost of survival signaling, derived from the underlying matrix. Live cell extrusion is essential for maintaining constant cell densities and preventing neoplasms,
as its disruption causes masses to rapidly form.
Triggers
Various factors such as
apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
,
overcrowding,
pathogens
In biology, a pathogen ( el, πάθος, "suffering", "passion" and , "producer of") in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a germ ...
and replicative stress can trigger extrusion from epithelia. Additionally, cells transformed with
oncogenic
Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abno ...
mutations such as
HRAS
GTPase HRas, from "Harvey Rat sarcoma virus", also known as transforming protein p21 is an enzyme that in humans is encoded by the gene. The ''HRAS'' gene is located on the short (p) arm of chromosome 11 at position 15.5, from base pair 522,241 t ...
and
Src can be ejected from epithelia by a similar extrusion process called Epithelial Defense Against Cancer (EDAC).
Signaling controlling extrusion
The rate limiting step for all types of cell extrusion discovered thus far is the production of the bioactive lipid,
Sphingosine 1-Phosphate
Sphingosine-1-phosphate (S1P) is a signaling sphingolipid, also known as lysosphingolipid. It is also referred to as a bioactive lipid mediator. Sphingolipids at large form a class of lipids characterized by a particular aliphatic aminoalcohol, ...
(S1P), which then binds the
G-protein-coupled receptor
G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...
,
S1P2 to trigger
Rho
Rho (uppercase Ρ, lowercase ρ or ; el, ρο or el, ρω, label=none) is the 17th letter of the Greek alphabet. In the system of Greek numerals it has a value of 100. It is derived from Phoenician letter res . Its uppercase form uses the sa ...
-mediated actin and myosin contraction at the base of the cell, propelling the cell out apically. Trafficking of S1P to the basolateral plasma membrane requires
microtubules
Microtubules are polymers of tubulin that form part of the cytoskeleton and provide structure and shape to eukaryotic cells. Microtubules can be as long as 50 micrometres, as wide as 23 to 27 nm and have an inner diameter between 11 an ...
, p115 RhoGEF and the plus-ended microtubule binding tumor suppressor
Adenomatous Polyposis Coli
Adenomatous polyposis coli (APC) also known as deleted in polyposis 2.5 (DP2.5) is a protein that in humans is encoded by the ''APC'' gene. The APC protein is a negative regulator that controls beta-catenin concentrations and interacts with E-c ...
(APC).
While the S1P-S1P2-Rho-actin/myosin axis apparently controls all extrusions, this axis can be activated by different signaling, depending on the stimulus. Apoptotic extrusion may activate S1P simply through caspase activation. However, live cell extrusion is activated by crowding dependent activation of the stretch-activated cation channel Piezo1.
Extrusion triggered by replicative stress
or by cell competition requires p53 activation.
Pathologies stemming from defective extrusion
Cancer
Disruption of extrusion not only leads to rapid formation of masses, a number of oncogenic mutations that drive aggressive cancers can hijack extrusion signaling in various ways to cause mass formation, disrupted barrier function, and aberrant Basal Cell Extrusion (BCE).
While most cells extrude apically out of the epithelia organs encase, BCE drives cells in the opposite direction--basally, which can enable them to invade through the underlying
stroma.
Cells transformed with KRas, a driver of pancreatic, and some types of lung and colon cancer, have unregulated
autophagy
Autophagy (or autophagocytosis; from the Ancient Greek , , meaning "self-devouring" and , , meaning "hollow") is the natural, conserved degradation of the cell that removes unnecessary or dysfunctional components through a lysosome-dependent re ...
, which degrades S1P and prevents apical extrusion. Instead, cells form masses at sites where they would normally extrude and, at completely separate sites invade by BCE.
Importantly, as they invade, BCE also causes the mechanical pinching off of their apical surfaces, which include epithelial determinants, thereby causing the cells to essentially partially de-differentiate.
Thus, oncogenic transformation can cause cells to mechanically de-differentiate and invade by hijacking a process that normally drives cell death. Similarly, mutations in APC mis-target S1P, also causing BCE.
Moreover, pancreatic cancers and some types of colon and lung cancer vastly down regulate S1P2.
Rescue of S1P2 alone is sufficient to reduce orthotopic pancreatic cancer and metastases in a mouse model.
Asthma
Whereas too little extrusion can lead to cancer, too much can drive inflammatory disease. Typically crowding of 1.6-fold causes live cells to extrude during homeostatic turnover. When epithelia experience pathological crowding, as airway epithelial do during an asthma attack, they can extrude at such high rates that it destroys the barrier they should provide.
This then mechanically causes the ensuing inflammation and hyper-susceptibility to infections that can follow an asthma attack. Because of this, blocking extrusion during an asthma attack may offer a new way to prevent this inflammatory period and potentially future attacks.
References
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Histology
Epithelial cells