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Jagu Barot
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Jagu Barot

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The Hallmarks of Cancer: 6 - Tissue Invasion and Metastasis

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 Sixth Hallmark of Cancer is defined as "Tissue Invasion and Metastasis". All five previous Hallmark articles can be found here: http://goo.gl/IDGfLp

A growing tumor will eventually spawn pioneer cells that move out of the original clump of mutant cells and travel to distant sites where they form new colonies. These distant settlements of cancer cells are named metastases. Metastases cause the majority of cancer deaths, and is therefore is bad news. But how do cancer cells migrate? As always, the full length article published on +Scientific American is a lot easier to follow and I highly recommend you check it out here: http://goo.gl/zw6GEQ

✤ Our tissues are not made up solely of cells. A large proportion of tissue consists of extracellular space, which is filled with a mixture of carbohydrate and protein molecules known as the Extra Cellular Matrix (ECM). The cells tether themselves to the ECM (and to each other) to form tissues. Metastasis therefore requires the untethering of these bonds, to allow predacious cancer cells to migrate freely. 

✤ Several classes of proteins are involved in the tethering of cells to their surroundings. The most important protein cementing cells to each other is known as E-cadherin. The coupling of cells by E-cadherin results in the transmission of antigrowth signals. Unsurprisingly, E-cadherin function is lost in migrating cancer cells. 

✤ What are the traits of migrating cancer cells? These cells change their appearance, from a neat, ordered cobblestone-like shape to spindly and long-limbed. The cells also untether themselves from the ECM and stop expressing E-cadherin, so that the cement which binds them to other cells is eliminated. A metastatic cancer cell has increased mobility and is resistant to cell death. These traits occur through the hijacking of a cellular program that promotes migration.

✤ Under normal circumstances, cells need to migrate during embryonic development. The primary pathway involved in this process is known as the Epithelial to Mesenchymal Transition, or EMT. Epithelial cells are surface cells that display a distinct polarity i.e. knowing which way is up due to being tethered to each other and the underlying ECM. In contrast, mesenchymal cells are loosely packed, have no polarity and are able to migrate freely. During embryonic development, epithelial cells are able to undergo physical and genetic changes collectively referred to as EMT. The resulting cells are migratory mesenchymal cells that have invasive properties. These cells are then recruited to specific sites in the developing embryo where they can revert back through MET (the reverse of EMT; Mesenchymal to Epithelial Transition) to form epithelial tissues at distant locations. 

✤ Cancer cells  hijack this process, first to enable metastasis through activating the EMT program, and then, once they reach their new home, to revert back to epithelial form by activating the MET program. Thus although the EMT-MET program has been known of in the context of embryonic development for many years, it is only recently that the significance of this EMT-MET program to cancer progression has been recognized.

✤ Metastasis has been traditionally thought of as the final stages of a burgeoning tumor; indeed, our current classification system for a tumor upon diagnosis assigns a higher value when there is evidence of metastasis.  We used to think that cancer cells pass through multiple successive mutations, growing in size, eventually sending away migratory cells to set up shop elsewhere. Dismayingly, recent evidence suggests that metastasis does not necessarily happen in the final stages of cancer progression, but can occur at any time. Sometimes even before the primary tumor is observed. The ability to invade and metastasize distant sites is a key hallmark of cancer progression, and possibly one of the most complicated and least understood hallmarks so far. 
 
#ScienceEveryday     #HallmarksOfCancer  
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