cancer – Australian Science

The Hallmarks of Cancer: Fighting Back

Buddhini Samarasinghe — Thu, 24 Oct 2013 00:12:09 +0000

Fighting back How can we use our knowledge about growth factors (detailed in the previous articles here and here) to fight back against cancer? This is where the magic words ‘targeted therapies’ come in. Since cancer cells hijack normal growth factor response pathways to become self sufficient, it is logical for us to target these errant pathways specifically. If a growth factor receptor is stuck on ‘always on’, for example as a perpetually active kinase, then finding a specific inhibitor to stop the activity of this kinase would starve the cancer cell of the signal it is dependent on for uncontrolled growth.

Glivec (as sold in Germany) is a specific kinase inhibitor. Inhibition of this kinase quells the sustained signaling required for uncontrolled growth and division of a cancer cell. Image credit: Wikimedia Commons.

Two such drugs, discovered in the 1990s utilize this principle. Gleevec, used as treatment for chronic myelogenous leukemia and Herceptin, for the treatment of breast cancer, both inhibit specific components of growth factor response pathways to starve the cancer of this signal. Earlier in this series I mentioned the Ras protein, which is frequently mutated in cancers; work is currently underway to find small molecules that are capable of inhibiting Ras. An exciting era of targeted cancer therapies lie ahead of us, because we have a deeper understanding of how cancer happens.

Cover of Time Magazine in May 2001. Image credit: Wikimedia Commons. Copyright: Time Magazine.

Cite this article:
Samarasinghe B (2013-10-24 00:12:09). The Hallmarks of Cancer: Fighting Back. Australian Science. Retrieved: May 18, 2024, from http://australianscience.com.au/biology/the-hallmarks-of-cancer-fighting-back/

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The Hallmarks of Cancer: Becoming Independent

Buddhini Samarasinghe — Mon, 16 Sep 2013 06:50:57 +0000

This article originally appeared on Know The Cosmos. I will be re-posting excerpts here for Australian Science with added commentary over the coming weeks!

“The Hallmarks of Cancer

Cite this article:
Samarasinghe B (2013-09-16 06:50:57). The Hallmarks of Cancer: Becoming Independent. Australian Science. Retrieved: May 18, 2024, from http://australianscience.com.au/biology/the-hallmarks-of-cancer-becoming-independent/

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The Hallmarks of Cancer: Growth Factors and Cell Signaling

Buddhini Samarasinghe — Mon, 09 Sep 2013 07:38:42 +0000

This article originally appeared on Know The Cosmos. I will be re-posting excerpts here for Australian Science with added commentary over the coming weeks!

“The Hallmarks of Cancer” are ten anti-cancer defense mechanisms that are hardwired into our cells, that must be breached by a cell on the path towards cancer. The First Hallmark of Cancer is defined as “Self-Sufficiency in Growth Signals”. What does this mean? In this post I will give an overview of growth factors and how they arhow growth signals are intimately involved in the development of cancer, it is necessary to define and understand what growth factors are, and explain how they control normal cellular behavior.

Growth Factors

Growth Factors are beautiful! This is a 3D schematic representation (also known as a ribbon diagram) of the structure of a growth factor known as Vascular Endothelial Growth Factor (VEGF). VEGF stimulates the development of new blood vessels, a process known as angiogenesis. Many large tumors secrete their own supply of VEGF in order to generate a supply line of oxygen-rich blood for the growing tumor to feed on. Image credit: Gizmag

Growth factors are, simply put, substances that control the multiplication of cells. There are many different types of growth factors, but they all have several characteristics in common. They are all proteins, and present at very low concentrations in tissues but with a high biological activity. They are responsible for controlling essential functions within the cell; growth, specialization and survival. Growth factors also do not circulate in the blood stream; instead, they act locally in areas near the cells that produce them. The image on the right shows a growth factor known as Vascular Endothelial Growth Factor (VEGF).

Cell Signaling

Growth Factors fit perfectly into Growth Factor Receptor Binding Sites. Two different types of Fibroblast Growth Factor (FGF1 and FGF2, left) shown bound to its specific receptor (center) and separate (right). Image credit: Alexander Plotnikov.

It is impossible to talk about growth factors and cancer without going over some of the basics of cell signaling. We are multi-cellular animals, and as such, our cells need to communicate with each other, so they can act in a coordinated manner in response to the environment. The basis of this communication comes from a process known as cell signaling.

The behavior of a cell depends on its immediate surrounding environment, known as the microenvironment. The assortment of growth factors in this microenvironment is the most important aspect regulating the behavior of that cell. All growth factors exert their effects by binding to a receptor. Receptors are proteins found on the surface of a cell that receive such chemical signals from the outside of the cell. Each growth factor has it’s own receptor; think of it as a key (the growth factor) fitting into a lock (the receptor). Growth factor receptors tend to be ‘transmembrane molecules’; this means that one end of the receptor ‘sticks out’ through the cell membrane into the microenvironment while the other end projects inside the cell. By spanning across the cell membrane, growth factor receptors are able to communicate signals from outside the cell (e.g. presence of growth factors in the microenvironment) to the inside of the cell. Revisiting the lock and key analogy, think of it as a key that fits into a lock that protrudes through the door-frame, instead of being flush against the door.

The binding of the growth factor to its specific receptor triggers a phosphorylation reaction inside the cell. Phosphorylation, or the addition of a phosphate group to a protein molecule, is an important step in cell signaling. This is because many proteins exist in an ‘on’ or ‘off’ state that can be switched by phosphorylation. Therefore, phosphorylation is a key step in regulating their activity. The enzymes that add phosphate groups to proteins are known as kinases; enzymes that remove phosphates are known as phosphatases. The exterior end of the receptor protein (the bit that sticks out of the cell) carries the growth factor binding site; the other end which projects inside the cell carries a kinase site. Binding of growth factor to the receptor binding site activates the kinase domain on the interior end of the receptor protein. This activated kinase, true to it’s name, then goes on to add phosphate groups to other proteins inside the cell, which then activate more proteins downstream, triggering a signaling cascade that finally ends with the activation of genes that bring about….you guessed it, cellular growth, specialization, or survival! The image below illustrates this process – I couldn’t find a decent one online so I made my own!

Mode of action of a typical Growth Factor. Growth Factor (red) binds to specific Growth Factor Receptor Binding Site (dark blue) on cell surface, which activates the kinase region (light blue). Activated kinase region now adds a phosphate group (yellow) to Protein 1 (blue) which activates it. Activated Protein 1 now adds a phosphate group to Protein 2 (green) further down the pathway, which activates it. Activated Protein 2 subsequently adds a phosphate group to Protein 3 (orange) which activates it. Activated Protein 3 moves through the nuclear membrane into the cell nucleus where it physically binds to the DNA and activates genes that control cell growth, specialization and survival. Image credit: Buddhini Samarasinghe

The description above is an extremely simplified version of what happens inside a cell; in reality, it is not so much a linear signaling pathway as it is an interwoven, intricate signaling web, with promiscuous proteins from many different pathways activating and repressing one another. The image below is not meant to frighten you (!) but rather to give you an idea how truly complex just one such signaling pathway, known as the MAPK/Erk pathway is.

A truly complex web of cell communication! These are some of the proteins we know that are involved in a single pathway known as the MAPK/Erk pathway. Signals from the outside of the cell go through this web of signaling, ultimately ending up with the activation of genes involved in growth, specialization and survival of the cell. Image credit: Cell Signaling Technology.

So there you have it. We’ve covered the basics of cell signaling and the molecular mechanisms that cause a cell to grow. Next time…I will explain what goes wrong with these processes in a cancer cell.

Cite this article:
Samarasinghe B (2013-09-09 07:38:42). The Hallmarks of Cancer: Growth Factors and Cell Signaling. Australian Science. Retrieved: May 18, 2024, from http://australianscience.com.au/biology/the-hallmarks-of-cancer-growth-factors-and-cell-signaling/

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The Ten Hallmarks of Cancer

Buddhini Samarasinghe — Tue, 03 Sep 2013 00:14:44 +0000

This series of articles originally appeared on Know The Cosmos. I will be reposting the articles here for AusSci with added commentary over the coming weeks!

In 2002, Robert Weinberg and Douglas Hanahan published a review article in the journal Cell titled “The Hallmarks of Cancer

Cite this article:
Samarasinghe B (2013-09-03 00:14:44). The Ten Hallmarks of Cancer. Australian Science. Retrieved: May 18, 2024, from http://australianscience.com.au/biology/the-ten-hallmarks-of-cancer/
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The Devil’s Technology

Ross Chapman — Fri, 27 Jul 2012 00:44:57 +0000

Biotechnology is rarely considered to be good for the environment. In fact, environmental campaigners frequently claim that genetically modified organisms represent a major threat to biodiversity and ecosystems. However, the study of the Tasmanian Devil Facial Tumour disease (DFTD) using genetic technologies is an example where biotechnology has been used to create a definite environmental benefit.

The Tasmanian Devil (Sarcophilius harrisi) is Australia’s largest surviving carnivore and endemic to the island of Tasmania. DFTD induces cancerous tumours on the face and inside the mouth of affected animals which die within months. The condition was first observed in north-eastern Tasmania in 1996. DFTD, like other cancers, is caused when mutations within a cell prompt it to switch from normal function into tumorous growth. Cancers are considered non-contagious as the tumour is contained within the body and is unable to spread to alternative hosts. Furthermore, the immune system of any alternative host would normally recognise any foreign tumour cells that managed to invade the body, and quickly kill them before the disease becomes established. However, the DFTD is exceptional in that it is readily transmitted between individuals of the same species, and this has resulted in the disease rapidly sweeping across the island and threatening the entire species with extinction.

In order to better understand the DFTD, an international team of scientists has sequenced the entire genome of the Tasmanian Devil and identified mutations underlying DFTD. The results were recently published in the scientific journal Cell. This biotechnological research surprisingly identified that none of the tumours originated in any of the hosts examined. Instead, they were able to trace them all back to one cancerous cell from within a female devil, possibly in the early 1990s. This radical and unusual tumour had developed the ability to jump from individual to individual in a uniquely contagious manner, so spreading the disease across the species.

The Tasmanina devil facial tumour.

Using the genetic sequence information, the researchers were able to discount the involvement of a virus in the transmission of DFTD. Instead they were able to identify a new and radical form of transmission. Devils often bite each other in the face during eating and feeding behaviours. During biting, fragments of tumour from an affected individual become implanted in an almost vampiric manner in a new and healthy individual.

The scientists also discovered that the DFTD tumour carries a mutation in a gene that plays a critical role in regulating the host’s immune reaction. From this, they concluded that the tumour cells are able to interfere with the host’s immune system immediately after implantation, The disrupted immune system is unable to kill the tumour, thereby ensuring the survival of the disease in the new individual.

The results of this study have provided valuable insight into the management of the DFTD and the conservation of the Tasmanian Devil. Because the condition is only transmitted through the bite from a diseased individual, the disease can be effectively controlled by quarantining healthy populations from diseased. The condition will then be naturally eliminated as diseased individuals die off from within the affected population. Such a policy has already been implemented with the Tasmanian Department of Primary Industries, Water and Environment who have been identifying and quarantining disease free populations within the island. Individuals from the protected population may then be re-introduced into the Tasmanian Devil’s former habitat once the disease threat has passed.

Despite the frequently cited threats that biotechnology poses to the environment, the application of gene sequencing technologies to the DFTD is an example of how biotechnology might be adopted to solve major environmental problems. In fact, the outcome of this gene sequencing project has contributed to a management plan that might yet save the Tasmanian Devil from extinction and conserve an important component of Australia’s unique biodiversity.

Image source

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