On any given weekend from March until October, it’s a fair bet that somewhere in your state there’s an event raising money for cancer treatment, prevention and/or research.  It probably seems, at times, like someone should have found a cure by now – after all, there has been an organized and concerted effort to cure this disease for the better part of the last century [1,2].  What is it about cancer that makes a cure so elusive, despite the efforts of innumerable hard-working and intelligent people?  It turns out we have spent a significant part of the last century underestimating just how clever cancer can be, but researchers and doctors are beginning to develop a better view of this disease, and as a result, are developing better treatments which may one day make cancer as treatable as any other chronic but manageable disease.

A Disease of a Thousand Faces

Cancer has traditionally been defined by the “parent cell” of the primary tumor – breast cancer is derived from cells found in the breast, pancreatic cancer comes from pancreatic cells, etc.  However, this created the misconception that all cancers within one of these classifications can be treated similarly.  Unfortunately, nothing is ever that simple with cancer.  There are actually tens if not hundreds of different types of cancer within each individual classification, making it necessary to treat what at first glance seemed to be one disease as an invasion caused by one of any number of different subtypes of cancer, each of which needs to be treated in a different way.

To further complicate things, most cancers, particularly solid tumors (a solid mass of cells in an organ – as opposed to liquid tumors, which are found in blood [3]), are actually small communities containing several subpopulations of cells, each of which has different characteristics.  This diversification typically happens as a by-product of the tumor’s development.  To become cancerous, a cell must acquire several types of mutations which allow it to become tumorous and ultimately deadly.  Most researchers believe that these mutations (changes in their genetic material) are acquired in a step-wise fashion (Figure 1), with each mutation compounding on previous mutations until the cell has evolved completely into a cancer cell – although there has been some evidence for other models that propose that cells can become cancerous in a single catastrophic event, wherein the genetic material is completely scrambled and then haphazardly stitched back together [4,5].  In the example shown below, an early mutation allows a cell to avoid the programmed “suicide,” by which normal cells are instructed to die when they realize they have sustained damage, as demonstrated by the green cells shown below.  Another defining characteristic of tumor cells is the ability to grow rapidly, so a subsequent mutation (shown in purple) may turn off genes for the receptors that would normally receive messages from nearby cells telling the cancer cell to stop growing.  The cell can now ignore all growth suppressing signals and grow exponentially without regard for its environment.  A third mutation (shown in red) could then allow some cells to move around, establishing the potential for metastasis, the process by which the cell moves to another site in the body. Ultimately, the diversity of cells with varying types and numbers of mutations within a single tumor gives rise to not one but several types of cancer colonizing the tumor site.

Figure 1. A tumor is not one type of cell but many.  The acquisition of mutations at different stages in the growth of the tumor allows for the existence of several subpopulations, which gives the tumor an advantage against drug treatments that only target a single type of mutation.

What Does This Mean for Treatment?

The existence of all those different cell types makes cancer particularly wily when you’re trying to eradicate it from someone’s body, and it’s often the culprit behind relapse after a treatment seems to have been successful.  Sometimes, killing off 90% of the cells that are susceptible to a drug simply allows room for the other 10% to take over – resulting in a population that is completely resistant to the first line of treatment.  Fortunately, researchers are now working to stay one step ahead of this particular survival technique by developing and designing multi-drug therapies that can target varied populations, theoretically wiping out all of the cells in the tumor.  There are, however, some drawbacks to this approach.  Since many treatments already have terrible side-effects, it is not always possible to combine drug treatments without causing too much harm to the patient.  As a result, some researchers have been experimenting with different approaches.

Breast cancer researchers at the University of Colorado Cancer Center have developed one novel procedure [6].  Many types of breast cancer are made primarily of hormone-receptor (HR) positive cells, meaning that these cells require estrogen (a hormone expressed highly in women’s bodies) to survive.  There are several treatments that are very successful at blocking these receptors, thus “starving” the cells of estrogen and largely killing the tumor.  However, if the patient has a subpopulation of HR negative cells, these will be immune to the hormone therapies.  Instead of trying to target these cells using a separate drug, researchers have forced the HR negative cells back into a lifestyle that requires estrogen.  Once this occurs, the cells are susceptible to the same hormone therapies that killed their HR positive neighbors.  Liken these HR negative cells to an organism that survives completely on meat; block its ability to eat meat, and it will resort to eating vegetables, at which point you can also blockade its ability to eat vegetables, causing it to die.  In the breast cancer example, the HR negative cells depend on another signaling molecule called Notch instead of estrogen, so researchers blocked the Notch receptors.  They found that doing this forced the tumor population back into a single, HR positive state, which could then be successfully targeted by anti-estrogen therapies.

Considering that cancer used to be treated as a single disease and that only one of its mutations – its ability to grow exponentially – was targeted, cancer therapies have come a long way.  Researchers can now test cancer for a variety of different “markers” that distinguish one subpopulation from another. Everyday there are more therapies being developed to target each subpopulation’s particular weaknesses, whether that means figuring out which drug combinations can be used to target all the cells in a patient’s tumor, or developing methods for forcing all of those cells to transform into a single population which can then be treated with a single therapy.  And while cancer has demonstrated time and again that its propensity to mutate often allows it to wiggle out of even the most specific therapies, research is making steady progress toward figuring out how to waylay these cells as they try to outmaneuver us, until eventually we will have a means of cutting off every avenue of escape.

Ilana Kelsey is a graduate student in biological and biomedical sciences at Harvard Medical School.

References

[1] Mukherjee, Siddhartha.  The Emperor of All Maladies: A Biography of Cancer.  New York: Scribner, 2010.

(Author’s Note: Interested in the history of science in general or the history of our fight against cancer in particular?  This is a really great, accessible book written by an Assistant Professor of Medicine at Columbia University.)

[2] Anders, Charlie Jane.  “Cancer is just as deadly as it was 50 years ago.  Here’s why that’s about to change.”  Io9 Backgrounder.  Gawker Media, 2011.  29 April 2012 <http://io9.com/5883180/why-havent-we-cured-cancer-yet>.

[3] “The Difference Between Liquid and Solid Tumors.”  National Comprehensive Cancer Network.  NCCN, 2012.  29 April 2012 <http://www.nccn.com/component/content/article/54-cancer-basics/1042-liquid-versus-solid-tumors.html>.

[4] Hanahan, Douglas and Weinberg, Robert A.  “Hallmarks of Cancer: The Next Generation.”  Cell 144.5 (2011): 646-674.

[5] Koboldt, Dan.  “Chromothripsis and Cancer.”  MassGenomics.  Daniel C. Koboldt, 2011.  29 April 2012 <http://massgenomics.org/2011/02/chromothripsis-and-cancer.html>.

[6] Sundem, Garth.  “Major finding: novel technique switches “triple-negative” breast cancer cells to more treatable, hormone-receptor positive cells.”  Colorado Cancer Blogs.  University of Colorado Cancer Center, 2012.  29 April 2012 < http://www.coloradocancerblogs.org/news/>.

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