Multicellularity, programmed cell death (apoptosis) and cancer

Way back in time

It was the  journey of one cell..

picture courtesy: http://www.visualphotos.com

One cell behaved as full and free organism in deep sea water
and moved on to a journey of evolution..

Multicellularity was the destined goal

And

Humans were the last one in this series to evolve
and roam on the land..

Much have changed ever since..

picture thankfully shared from:

http://www.bbc.co.uk/nature/

history_of_the_earth

But..

We still have memories in each individual cell stored and intact, 

like..

1. Our cells still do all life-activities in water..

2. Our multicellular journey in embryonic stage still starts with one cell, 
bearing all features of their predecessor species at one or other stage..
(i.e. ontogeny repeats phylogeny)

3. And before coming to land, we still swim in sea-like water of amniotic fluid in mother's womb..

But..

Multicellularity has come up with unique features
for combined survival of trillions
of cell-fellows
for a common-cause,

like..

1. Multicellularity is the ultimate in cooperation,
multiple cells make up an individual
that cooperates for the benefit of the whole. 

 Sometimes cells give up their ability to reproduce for the benefit of close kin..

2. Cells present in multicellular organisms possess the unique property of self-destruction.
They have the genetic information to commit suicide !
This phenomenon is termed as programmed cell death (PCD).
That way stressed and damaged cells kill them self for the benefit of whole..

And.. 

If a single cell negates this self sacrifice....

then it causes cancer, 

And..

The whole lot of cells in an individual body are doom to die

And 

Individuals have to perish !!

Apoptosis: The cells of a multicellular organism are members of a highly organized community. The number of cells in this community is tightly regulated—not simply by controlling the rate of cell division, but also by controlling the rate of cell death. If cells are no longer needed, they commit suicide by activating an intracellular death program.

The balance between the formation 

of new cells and deletion of the old 

and abnormal cells is vital for all 

physiological processes of the body.

Credit: NIH

This process is therefore called programmed cell death, although it is more commonly called apoptosis (from a Greek word meaning “falling off,” as leaves from a tree).

The most mind-boggling 

phenomenon in cells is the 

mechanism through which they 

determine their own age, and 

when old enough and susceptible 

to damage, they commit suicide. 

Every single day, millions of cells 

die and are replaced by new cells

―a process called cell turnover.

courtesy share:http://www.buzzle.com/

articles/why-do-cells-commit-suicide.html

Necrosis and Apoptosis: Cells that die as a result of acute injury typically swell and burst. They spill their contents all over their neighbors—a process called cell necrosis—causing a potentially damaging inflammatory response. By contrast, a cell that undergoes apoptosis dies neatly, without damaging its neighbors. The cell shrinks and condenses. The cytoskeleton collapses, the nuclear envelope disassembles, and the nuclear DNA breaks up into fragments. Most importantly, the cell surface is altered, displaying properties that cause the dying cell to be rapidly phagocytosed, either by a neighboring cell or by a macrophage (a specialized phagocytic cell), before any leakage of its contents occurs. This not only avoids the damaging consequences of cell necrosis but also allows the organic components of the dead cell to be recycled by the cell that ingests it.

Intracellular regulators of the cell death program: All nucleated animal cells contain the seeds of their own destruction, in the form of various inactive procaspases that lie waiting for a signal to destroy the cell. It is therefore not surprising that caspase activity is tightly regulated inside the cell to ensure that the death program is held in check until needed.

Mitochondrial role in apoptosis: When cells are damaged or stressed, they can also kill themselves by triggering procaspase aggregation and activation from within the cell. In the best understood pathway, mitochondria are induced to release the electron carrier protein cytochrome c  into the cytosol, where it binds and activates an adaptor protein called Apaf-1. This mitochondrial pathway of procaspase activation is recruited in most forms of apoptosis to initiate or to accelerate and amplify the caspase cascade. DNA damage, for example, can trigger apoptosis. This response usually requires p53, which can activate the transcription of genes that encode proteins that promote the release of cytochrome c from mitochondria. These proteins belong to the Bcl-2 family.
(http://www.ncbi.nlm.nih.gov/books/NBK26873/)

Cell suicide related disorder: One of the most disastrous consequences of failure in cell suicide is the dreadful set of diseases called cancer. Other conditions or disorders include congenital defects, like syndactyly (fused fingers), neural tube malformation, skeletal system defects, etc., as well as several autoimmune disorders. On the contrary, early triggering of cell suicide leads to degenerative disorders of the nervous and skeletal systems. (http://www.buzzle.com/articles/why-do-cells-commit-suicide.html)

Apoptosis and Cancer

Some viruses associated with cancers use tricks to prevent apoptosis of the cells they have transformed.

• Several human papilloma viruses (HPV) have been implicated in causing cervical cancer. One of them produces a protein (E6) that binds and inactivates the apoptosis promoter p53.
• Epstein-Barr Virus (EBV), the cause of mononucleosis and associated with some lymphomas
  • produces a protein similar to Bcl-2
  • produces another protein that causes the cell to increase its own production of Bcl-2. Both these actions make the cell more resistant to apoptosis (thus enabling a cancer cell to continue to proliferate).

Even cancer cells produced without the participation of viruses may have tricks to avoid apoptosis.

• Some B-cell leukemias and lymphomas express high levels of Bcl-2, thus blocking apoptotic signals they may receive. The high levels result from a translocation of the BCL-2 gene into an enhancer region for antibody production.
• Melanoma (the most dangerous type of skin cancer) cells avoid apoptosis by inhibiting the expression of the gene encoding Apaf-1.
• Some cancer cells, especially lung and colon cancer cells, secrete elevated levels of a soluble "decoy" molecule that binds to FasL, plugging it up so it cannot bind Fas. Thus, cytotoxic T cells (CTL) cannot kill the cancer cells.
• Other cancer cells express high levels of FasL, and can kill any cytotoxic T cells (CTL) that try to kill them because CTL also express Fas (but are protected from their own FasL) 

What makes a cell decide to commit suicide?

The balance between:

• the withdrawal of positive signals; that is, signals needed for continued survival, and
• the receipt of negative signals.

Withdrawal of positive signals

The continued survival of most cells requires that they receive continuous stimulation from other cells and, for many, continued adhesion to the surface on which they are growing. Some examples of positive signals:

• growth factors for neurons
• Interleukin-2 (IL-2), an essential factor for the mitosis of lymphocytes

Receipt of negative signals

• increased levels of oxidants within the cell
• damage to DNA by these oxidants or other agents like
  • ultraviolet light
  • X-rays
  • chemotherapeutic drugs
• accumulation of proteins that failed to fold properly into their proper tertiary structure
• molecules that bind to specific receptors on the cell surface and signal the cell to begin the apoptosis program. These death activators include:
  • Tumor necrosis factor-alpha (TNF-α) that binds to the TNF receptor;
  • Lymphotoxin (also known as TNF-β) that also binds to the TNF receptor;
  • Fas ligand (FasL), a molecule that binds to a cell-surface receptor named Fas (also called CD95). 
  (http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/A/Apoptosis.html) 

Sydney Brenner, H. Robert Horvitz and John Sulston were awarded the Nobel Prize in Physiology or Medicine in 2002 "for their discoveries concerning genetic regulation of organ development and programmed cell death."
― Nobelprize.org

some blog post links related with multicellularity, nature of mitochondria and viruses, cancer cause and cure.

http://sciencedoing.blogspot.in/2012/02/cell-multicellularity-in-new.html

http://sciencedoing.blogspot.in/2013/02/mitochondrion-cell-organelle-symbiotic.html

http://sciencedoing.blogspot.in/2013/03/viruses-are-cellular-organisms.html  

http://sciencedoing.blogspot.in/2014/03/100000-viruses-hid-in-human-genes.html

http://sciencedoing.blogspot.in/2013/12/cancer-cell-behaving-as-organism.html

http://sciencedoing.blogspot.in/2013/12/cancer-deeper-cellular-chemistry-and.html

http://sciencedoing.blogspot.in/2013/12/cancer-reasons-behind-unruly-behaviour.html

http://sciencedoing.blogspot.in/2013/12/cancer-non-communicable-disease-on-rise.html 

http://sciencedoing.blogspot.in/2014/05/dca-treatment-of-cancer-by-inducing.html

http://sciencedoing.blogspot.in/2014/05/fragile-sites-during-dna-replication.html

Fragile sites during DNA replication (mitosis) could be possible places of cancer

Faulty DNA copying machine may print cancer 
during mitosis !!

A glitch in copying the 46 chromosomes every time a cell divides can leave gaps or breaks, giving rise to chromosomal rearrangements at “fragile sites” that could act as breeding ground for cancer, according to a study.

The “fragile sites” appear in specific areas of the genome where the DNA-copying machinery is slowed or stalled, either by certain sequences of DNA or by structural elements.

"The study is the first to examine thousands of these (fragile) sites across the entire genome and ask what they might have in common," said Thomas Petes, a professor of molecular genetics and microbiology at Duke University School of Medicine in the US.(http://www.daijiworld.com/news/news_disp.asp?n_id=233126)

"Other studies have been limited to looking at fragile sites on specific genes or chromosomes," said* Thomas D. Petes, Ph.D., a Minnie Geller professor of molecular genetics and microbiology at Duke. "Ours is the first to examine thousands of these sites across the entire genome and ask what they might have in common."

In their study, which was published recently in the journal**  Proceedings of the National Academy of Sciences, the team discovered a potential method on how to fully understand the genetic abnormalities underlying many solid tumors.(http://www.techtimes.com/articles/6646/20140507/dna-copying-machinery-flaw-on-fragile-sites-make-individuals-more-prone-to-cancer.htm)

original research references:

*Where DNA's copying machine pauses, cancer could be next

**Genome-wide high-resolution mapping of chromosome fragile sites

#above cited three pictures thankfully shared from:http://www.vcbio.science.ru.nl/en/virtuallessons/cellcycle/trans/

WHO calls for action on antibiotic resistant gram negative organisms (superbugs)

WHO's first global report [1] on antibiotic resistance reveals serious, worldwide threat to public health:

A new report by WHO–its first to look at antimicrobial resistance, including antibiotic resistance, globally–reveals that this serious threat is no longer a prediction for the future, it is happening right now in every region of the world and has the potential to affect anyone, of any age, in any country. Antibiotic resistance–when bacteria change so antibiotics no longer work in people who need them to treat infections–is now a major threat to public health.

Many bacterial infections, such as gonorrhea 

(microscopic image above), are no longer easily 

treated with antibiotics.

Photograph by science picture co., corbis

#thankfully shared from:Nat Geo

Concern of the day:
“Without urgent, coordinated action by many stakeholders, the world is headed for a post-antibiotic era, in which common infections and minor injuries which have been treatable for decades can once again kill,” says Dr Keiji Fukuda, WHO’s Assistant Director-General for Health Security. “Effective antibiotics have been one of the pillars allowing us to live longer, live healthier, and benefit from modern medicine. Unless we take significant actions to improve efforts to prevent infections and also change how we produce, prescribe and use antibiotics, the world will lose more and more of these global public health goods and the implications will be devastating.”

thankfully shared from:http://myemail.constantcontact.com/
Scary-story-on-Halloween-.html?soid=1103767629821&aid
=5SfYC3niN_M

Key findings from the report include:

• Resistance to the treatment of last resort for life-threatening infections caused by a common intestinal bacteria, Klebsiella pneumoniae–carbapenem antibiotics–has spread to all regions of the world. K. pneumoniae is a major cause of hospital-acquired infections such as pneumonia, bloodstream infections, infections in newborns and intensive-care unit patients. In some countries, because of resistance, carbapenem antibiotics would not work in more than half of people treated for K. pneumoniae infections.
• Resistance to one of the most widely used antibacterial medicines for the treatment of urinary tract infections caused by E. coli–fluoroquinolones–is very widespread. In the 1980s, when these drugs were first introduced, resistance was virtually zero. Today, there are countries in many parts of the world where this treatment is now ineffective in more than half of patients.
• Treatment failure to the last resort of treatment for gonorrhoea–third generation cephalosporins–has been confirmed in Austria, Australia, Canada, France, Japan, Norway, Slovenia, South Africa, Sweden and the United Kingdom. More than 1 million people are infected with gonorrhoea around the world every day.
• Antibiotic resistance causes people to be sick for longer and increases the risk of death. For example, people with MRSA (methicillin-resistant Staphylococcus aureus) are estimated to be 64% more likely to die than people with a non-resistant form of the infection. Resistance also increases the cost of health care with lengthier stays in hospital and more intensive care required.

 People can help tackle resistance by:

• using antibiotics only when prescribed by a doctor;
• completing the full prescription, even if they feel better;
• never sharing antibiotics with others or using leftover prescriptions.

Health workers and pharmacists can help tackle resistance by:

• enhancing infection prevention and control;
• only prescribing and dispensing antibiotics when they are truly needed;
• prescribing and dispensing the right antibiotic(s) to treat the illness.

Policymakers can help tackle resistance by:

• strengthening resistance tracking and laboratory capacity;
• regulating and promoting appropriate use of medicines.

Policymakers and industry can help tackle resistance by:

• fostering innovation and research and development of new tools;
• promoting cooperation and information sharing among all stakeholders.

 

Highlights of the report by WHO South-East Asia Region

The available data reveal that antibiotic resistance is a burgeoning problem in WHO’s South-East Asia Region, which is home to a quarter of the world’s population. The report’s results show high levels of E. coli resistance to third generation cephalosporins and fluoroquinolones—two important and commonly used types of antibacterial medicine–in the Region. Resistance to third generation cephalosporins in K. pneumoniae is also high and widespread. In some parts of the Region, more than one quarter of Staphylococcus aureus infections are reported to be methicillin-resistant (MRSA), meaning that treatment with standard antibiotics does not work. In 2011, the health ministers of the Region articulated their commitment to combat drug resistance through the Jaipur Declaration. Since then, there has been growing awareness of the need for appropriate tracking of drug resistance, and all countries have agreed to contribute information to a regional database. Dr Poonam Khetrapal Singh, WHO Regional Director for South-East Asia, has identified drug resistance as a priority area of WHO’s work in the Region.

#antibiotic crisis and molecular medicine

#content of this post thankfully shared from a news link of WHO, 30 April 2014 Geneva: http://www.who.int/mediacentre/news/releases/2014/amr-report/en/ 

DCA treatment of cancer by inducing apoptosis

Scientists cure cancer but no one takes notice

Canadian scientists (metabolic modulation of glioblastoma with dichloroacetate) tested this dichloroacetate (DCA) on human's cells; it killed lung, breast and brain cancer cells and left the healthy cells alone. It was tested on Rats inflicted with severe tumors; their cells shrank when they were fed with water supplemented with DCA. The drug is widely available and the technique is easy to use, why the major drug companies are not involved? Or the Media interested in this find? 

Cheap, 'safe' drug kills most cancers

It sounds almost too good to be true: a cheap and simple drug that kills almost all cancers by switching off their "immortality". The drug, dichloroacetate (DCA), has already been used for years to treat rare metabolic disorders and so is known to be relatively safe.

DCA attacks a unique feature of cancer cells: the fact that they make their energy throughout the main body of the cell, rather than in distinct organelles called mitochondria. This process, called glycolysis, is inefficient and uses up vast amounts of sugar.

Until now it had been assumed that cancer cells used glycolysis because their mitochondria were irreparably damaged. However, Michelakis's experiments prove this is not the case, because DCA reawakened the mitochondria in cancer cells. The cells then withered and died (Cancer Cell, DOI: 10.1016/j.ccr.2006.10.020).

Michelakis suggests that the switch to glycolysis as an energy source occurs when cells in the middle of an abnormal but benign lump don't get enough oxygen for their mitochondria to work properly. In order to survive, they switch off their mitochondria and start producing energy through glycolysis.

Crucially, though, mitochondria do another job in cells: they activate apoptosis, the process by which abnormal cells self-destruct. When cells switch mitochondria off, they become "immortal", outliving other cells in the tumour and so becoming dominant. Once reawakened by DCA, mitochondria reactivate apoptosis and order the abnormal cells to die.

"The results are intriguing because they point to a critical role that mitochondria play: they impart a unique trait to cancer cells that can be exploited for cancer therapy," says Dario Altieri, director of the University of Massachusetts Cancer Center in Worcester.

The phenomenon might also explain how secondary cancers form. Glycolysis generates lactic acid, which can break down the collagen matrix holding cells together. This means abnormal cells can be released and float to other parts of the body, where they seed new tumours.

Cancer cell

Cancer progression and its resistance to treatment depend, at least in part, on suppression of apoptosis. Although mitochondria are recognized as regulators of apoptosis. In 1930, Warburg suggested that mitochondrial dysfunction in cancer results in a characteristic metabolic phenotype, that is, aerobic glycolysis (Warburg, 1930).

picture courtesy:http://www.sott.net/article/
228583-Scientists-cure-cancer-but-no-one-takes-notice  

Positron emission tomography (PET) imaging has now confirmed that most malignant tumors have increased glucose uptake and metabolism. This bioenergetic feature is a good marker of cancer but has not been therapeutically pursued, as it is thought to be a result and not a cause of cancer; that is, the cells rely mostly on glycolysis for energy production because of permanent mitochondrial damage, preventing oxidative phosphorylation. However, whether the mitochondria in cancer are indeed damaged and whether this is reversible remain unknown. (http://www.sciencedirect.com/science/article/pii/S1535610806003722)

Cancer mitochondria are hyperpolarized and have suppressed oxidative metabolism, both of which are reversed by DCA

The small molecule DCA is a metabolic modulator that has been used in humans for decades in the treatment of lactic acidosis and inherited mitochondrial diseases. Without affecting normal cells DCA reverses the metabolic-electrical remodeling, inducing apoptosis and decreasing tumor growth. 

picture courtesy:http://www.sciencedirect.com/
science/article/pii/S1535610806003722  

DCA in the drinking water at clinically relevant doses for up to 3 months prevents and reverses tumor growth in vivo, without apparent toxicity and without affecting hemoglobin, transaminases, or creatinine levels. The ease of delivery, selectivity, and effectiveness make DCA an attractive candidate for proapoptotic cancer therapy which can be rapidly translated into phase II-III clinical trials. (http://www.sciencedirect.com/science/article/pii/S1535610806003722)

Paul Clarke, a cancer cell biologist at the University of Dundee in the UK, says the findings challenge the current assumption that mutations, not metabolism, spark off cancers. "The question is: which comes first?" he says.

Note:Text and pictures were thankfully shared from their original sources as listed below:

http://www.sott.net/article/228583-Scientists-cure-cancer-but-no-one-takes-notice

http://stm.sciencemag.org/content/2/31/31ra34.abstract

http://www.newscientist.com/article/dn10971-cheap-safe-drug-kills-most-cancers.html#.U2MTU5Fb2Sq

http://www.sciencedirect.com/science/article/pii/S1535610806003722