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: Apr 28, 2024, from http://australianscience.com.au/biology/the-hallmarks-of-cancer-fighting-back/

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The post The Hallmarks of Cancer: Fighting Back appeared first on Australian Science.

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: Apr 28, 2024, from http://australianscience.com.au/biology/the-hallmarks-of-cancer-growth-factors-and-cell-signaling/

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The post The Hallmarks of Cancer: Growth Factors and Cell Signaling appeared first on Australian Science.

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: Apr 28, 2024, from http://australianscience.com.au/biology/the-ten-hallmarks-of-cancer/
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The post The Ten Hallmarks of Cancer appeared first on Australian Science.

hallmarks of cancer – Australian Science

The Hallmarks of Cancer: Fighting Back

The Hallmarks of Cancer: Growth Factors and Cell Signaling

Growth Factors

Cell Signaling

The Ten Hallmarks of Cancer