Blebbishield emergency program is a process which acts as a last line of defense for cancer stem cells after induction of

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 ...

where the apoptotic blebs fuse to shield the cells/nucleus from the destructive force of apoptosis by forming blebbishields. Blebbishields in turn fuse to each other and generate cancer stem cell spheres/cellular transformation, essentially shifting the balance of dying cells back towards survival. BS-Fig1

Discovery

Blebbishields were first identified in human

bladder cancer Bladder cancer is any of several types of cancer arising from the tissues of the urinary bladder. Symptoms include blood in the urine, pain with urination, and low back pain. It is caused when epithelial cells that line the bladder become mali ...

cell lin
RT4
(HTB-2: ATCC), referred to as RT4P (RT4 parent) in the initial report. Jinesh GG, Choi W, Shah JB, Lee EK, Willis DL, Kamat AM

Cell Death Differ. 2013 Mar;20(3):382-95.

Blebbishield formation

Every cell type, especially cancer cells, are capable of undergoing apoptosis, a process in which the

plasma membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment (t ...

undergoes blebbing followed by orderly deconstruction of cells into apoptotic bodies. Cancer stem cells have the extraordinary ability to construct blebbishields from these apoptotic bodies by bleb-bleb fusion and form stem cell spheres/cellular transformation by sub-sequent blebbishield-blebbishield fusion. Endocytosis and endocytosis-drive
serpentine filopodia
are necessary to tether and tie apoptotic bodies to facilitate fusion.Jinesh GG, & Kamat AM
Endocytosis and serpentine filopodia drive blebbishield-mediated resurrection of apoptotic cancer stem cells
Cell Death Discovery 2016 Jan;2: 201569. The involvement of

membrane fusion A membrane is a selective barrier; it allows some things to pass through but stops others. Such things may be molecules, ions, or other small particles. Membranes can be generally classified into synthetic membranes and biological membranes. B ...

was confirmed by inhibiting

cholesterol Cholesterol is any of a class of certain organic molecules called lipids. It is a sterol (or modified steroid), a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell mem ...

using the cholesterol antagonist Filipin-III.

Blebbishields and cancer stem cells

Sphere forming cells widely display characteristics of

tumorigenesis 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 ...

. Cells from blebbishield derived spheres are tumorigenic in nature, providing an important clue for tumorigenesis. Blebbishield emergency program is postulated to have the strong rationale for bladder cancer recurrence as it is a potential cause for multifocal/satellite bladder tumors. The blebbishield derived cells exhibit strong drug resistance behavior and exhibit high sensitivity to Hoechst-33342 similar to side-population cells.

Positive and negative regulators of blebbishield survival

Caspases

Caspases ( Caspase-3, caspase-8, caspase-9) are found to have important roles in contributing the formation of blebbishields as well as sub-sequent cancer stem cell spheres. Caspase-3 plays a dual role where it is needed for induction of proper apoptosis: to activate Bax and Bak by cleavage to kill the cells and also needed for transformation from blebbishields.Jinesh GG, Molina JM, Huang L, Laing NM, Mills GB, Bar-Eli M & Kamat AM
Mitochondrial oligomers boost glycolysis in cancer stem cells to facilitate blebbishield-mediated transformation after apoptosis
Cell Death Discovery 2016 Feb;2: 20163.

VEGF signaling

VEGF Vascular endothelial growth factor (VEGF, ), originally known as vascular permeability factor (VPF), is a signal protein produced by many cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors, ...

signaling, especially VEGF-A to VEGFR2 signaling plays a commanding role during the transformation from blebbishields. VEGF signaling leads to IRES translation of N-Myc, which in concert wit
mitochondrial oligomers
to boost glycolysis to power blebbishield formation and transformation from blebbishields.

Lactic acid Lactic acid is an organic acid. It has a molecular formula . It is white in the solid state and it is miscible with water. When in the dissolved state, it forms a colorless solution. Production includes both artificial synthesis as well as natu ...

, a tumor derived metabolite, altering pH of

tumor microenvironment The tumor microenvironment (TME) is the environment around a tumor, including the surrounding blood vessels, immune cells, fibroblasts, signaling molecules and the extracellular matrix (ECM). The tumor and the surrounding microenvironment are cl ...

enhances sphere formation from blebbishields positively regulating VEGF bioavailability.

Reactive oxygen species OS/h2>
Reactive oxygen species plays a role in cellular transformation. Various PKC isoforms were implicated in p47phox/Nox1 axis mediated ROS generation during cellular transformation. PKC-ζ isoform interaction with p47phox was found to be critical for ROS production and transformation from blebbishields.

Role of mitochondria and Glycolysis in blebbishield emergency program

Protection of

mitochondria A mitochondrion (; ) is an organelle found in the Cell (biology), cells of most Eukaryotes, such as animals, plants and Fungus, fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosi ...

from outer membrane permeabilization is important to retain the transforming potential of blebbishields.Jinesh GG, Laing NM, & Kamat AM
Smac mimetic with TNF-α targets Pim-1 isoforms and reactive oxygen species production to abrogate transformation from blebbishields
Biochemical Journal 2016 Jan; 473 (1):99-107. Functional mitochondria lead to uninterrupted glycolysis which in turn protects the blebbishields from secondary necrosis.

K-Ras ''KRAS'' (Kirsten rat sarcoma virus) is a gene that provides instructions for making a protein called K-Ras, a part of the RAS/MAPK pathway. The protein relays signals from outside the cell to the cell's nucleus. These signals instruct the cell ...

BAD Bad or BAD may refer to: Common meanings *Evil, the opposite of moral good * Erroneous, inaccurate or incorrect * Unhealthy, or counter to well-being * Antagonist, the threat or obstacle of moral good Acronyms * BAD-2, a Soviet armored troll ...

(phosphorylated at Ser-112), p27, Bax and

Bak Bak or BAK may refer to: Computer * Bak file * ''Betrayal at Krondor'', a DOS-based role-playing video game * Bill and keep reciprocal payment in telecommunications systems Acronyms * Bcl-2 homologous antagonist killer, a protein involved in pro ...

forms oligomers to boost

glycolysis Glycolysis is the metabolic pathway that converts glucose () into pyruvate (). The free energy released in this process is used to form the high-energy molecules adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide (NADH ...

, which in turn overrides secondary necrosis and offer energy required to proceed with the reconstruction process during cellular transformation from blebbishields.

Other factors

N-linked glycosylation ''N''-linked glycosylation, is the attachment of an oligosaccharide, a carbohydrate consisting of several sugar molecules, sometimes also referred to as glycan, to a nitrogen atom (the amide nitrogen of an asparagine (Asn) residue of a protein), ...

and v-ATPase were implicated to have survival roles in blebbishield emergency program.

References

{{Reflist Cancer pathology Stem cells