The Absence

Cancer is the enemy within. A subset of cells in our own bodies, equipped with little more than the same genes and proteins present in all of our cells, begin a quiet rebellion. The insurrection commences under the radar, lacking the formality of the United States Declaration of Independence or the ostentation of the bombardment of Fort Sumter. Still, quietly and methodically, these contumacious ne’er-do-wells begin to push back against the controls, checks, and balances that our bodies place upon all cells. Slowly and firmly, they reply to these control mechanisms with a simple word.

“No.”

What they’re rejecting are the instructions our bodies give to our cells (and cells give one another) concerning when, where, and how to grow and divide. After all, our bodies contain trillions of cells (nearly 100 trillion in the adult human body), all born with the same set of genetic instructions, and all working together toward a common goal: building a functional human being. This delicate and coordinated effort is mediated, in part, by instructions given to cells, telling them when to devote time and energy into different efforts: growing, dividing, and even dying. These instructions come from other cells or the cell itself, and are all ultimately encoded in the genes that make up our genome. It’s hard to coordinate the activity of trillions of cells in dozens of different tissues and organs. But ultimately, the entire process can be boiled down to these simple instructions for each cell. For example, one (simplified) set of instructions might read: divide here, spend some time growing, divide again, differentiate into a neuron, grow some more, then stop and just do your job as long as you’re able to. In the context of a complex organ, or even an entire human being, these are tiny moves. But, combined with trillions of tiny other moves, they make a functional and unique life form.

The cells of the insurrection, beginning with their persistent “No”, ignore and later oppose the coordinated messages cells generate for themselves (and receive from other cells) to coordinate their activity with the activity of the other 100 trillion cells in the body. The rebels begin to grow and divide on their own, ignoring messages from the rest of the body, and circumventing the body’s efforts to shut them down. That’s what cancer is, after all: misregulated cell division in a tissue or organ, ultimately yielding a malignant tumor which spreads throughout the body.

Mutations lie at the heart of this rebellion. A cell can lose the ability to regulate its growth and division, or respond to signals from the rest of the body, if mutations occur in the genes that govern these processes.  As I’ve noted before, the term “mutation” simply refers to changes that occur every now and then in our genomes. Most mutations don’t appear to be harmful, and many serve as the basis for evolution. But sometimes, deleterious mutations occur in genes that have critical functions. There are genes, for example, that tell a cell to avoid dividing until the cell has duplicated its genome, surveyed those duplicate copies for large-scale errors, repaired them, grown sufficiently, and received the necessary number of internal and external “go signals” for cell division. These genes are generally referred to as tumor suppressor genes. If deleterious mutations occur in some tumor suppressor genes, then a cell could divide more often than it should. Since tumor suppressor genes also help cells detect and repair damage to their genes, mutations in tumor suppressor genes could keep the cell from fixing other mutations as they occur, leading to a gradual increase in the number of mutations in this rapidly dividing population of cells.

Mutations in tumor suppressor genes are just one mechanism by which cells can begin to say “No”. There are many others. For example, in normal cells, genes called proto-oncogenes promote cell division when the time is right (and when tumor suppressor genes give the “all clear” signal). But, if a deleterious mutation in a proto-oncogene increases its level of activity, or causes it to ignore signals from tumor suppressor genes, then a cell will grow and divide when it shouldn’t. Since these mutations (whether they’re in tumor suppressor genes, proto-oncogenes, or other genes) are embedded in the cell’s genome, they’re passed on to daughter cells, spreading these mutations. In addition, since these mutations weaken the cell’s ability to detect and repair other mutations in the genome, more mutations can accumulate in these rebellious cells, further increasing their division cycles.

From the above examples of proto-oncogenes and tumor suppressor genes, you may be seeing a pattern: there are many ways to break a cell’s ability to regulate its growth and division. These mechanisms can initiate a type of feed-forward loop. A weakened tumor suppressor system or heightened proto-oncogene division signal cause a cell to divide when it shouldn’t, and faster than it should. The increased speed of cell divisions makes essential steps of a cell’s life (like genome replication) more sloppy, leading to more mutations. Eventually, these rebellious cells become so quick and so careless in their cycles of growth and division that they begin to shed whole sections of their genomes on their journey toward a cancerous state. As much as 10% of genes are completely absent in some cancer cells. Other genes are replicated more than they ought to be, leading to increased cellular activity of these genes. Some of the genes that are often deleted include tumor suppressor genes, while cancer cells have many extra replicated copies of proto-oncogenes.  What began as a simple and firm “No” becomes an emphatic “HELL NO!!!”

Regardless of tissue, scientists see this pattern in most types of cancers: shedding weakened tumor suppressor genes, amplifying mutated proto-oncogenes, dividing in a seemingly uncontrollable fashion, and ignoring every instructive “stop” signal the body sends to tumors. Much research focuses on these proto-oncogenes and tumor suppressor genes, and many cancer therapies to date have targeted these genes. For decades, it has been the hope of medicine that an effective treatment for cancer lies in restoring the activity of tumor suppressor genes and dampening the activity of proto-oncogenes. The hope has waned, however, with the realization that different types of tumors (brain vs. skin) harbor very different patterns of gene shuffling and deletion. Thus, medicine has also focused on efforts to increase the patient’s immune response against cancer cells, therapeutics that exploit some of the metabolic oddities of cancer cells, or “out of the box” remedies that we’ve never considered.

One such “out of the box” remedy has just been published in the journal Nature. A team of scientists from the University of Texas MD Anderson Cancer Center, the Dana-Farber Cancer Institute, the Memorial Sloan Kettering Cancer Center, and Harvard Medical School tested a new potential target for cancer therapeutics, with promising results. Their target has been known for quite some time: it is the large-scale genome rearrangements and deletions cells undergo in their journey from being wayward dividers to malignant tumors. They didn’t look at the tumor suppressor genes that are often eliminated. Instead, they focused on the so-called “collateral damage” of this hasty genome rearrangement: innocent “passenger” genes that are thrown out alongside the tumor suppressor genes.

Genes often aren’t arranged in a “logical” order within our genomes. It’s not uncommon to find neighboring genes that have absolutely nothing to do with one another. For example, a gene critical for the immune system could reside next to a gene required for the proper development of muscle fibers. Tumor suppressor genes are no different. They reside in many locations throughout the genome, and many of their neighboring genes have functions unrelated to cell division. Yet, in a rebellious “No” cell’s haste to throw out tumor suppressor genes, they often discard lots of neighboring genes. Of course, if the cell accidentally discarded any gene essential for cell function, it would die. But, many cancer cells still get away with discarding large sections of the genome. One reason they can discard so much has to do with the specificity of cancer cell types: a cancerous nerve cell could theoretically discard genes required for muscle development without causing too much trouble. Another reason is redundancy. Often, for any given cellular function, the human genome is equipped with multiple genes that can execute that function. So, if one gene copy is lost to mutation, for example, another copy can step up to take its place.

The team reporting in this Nature study exploited this latter point of redundancy. They looked at a widely-studied form of brain tumor called a glioblastoma. Most forms of glioblastoma undergo similar types of genome rearrangement (including deletions) in their journey toward forming aggressive and invasive tumors. One of the deletions common in glioblastoma involves the loss of a tumor suppressor gene and many of its neighboring genes. One of these “passenger” genes that is lost is called ENO1. The ENO1 gene normally instructs nerve cells to make a protein called enolase, which is required to metabolize sugar and obtain energy. Thus, ENO1 is a fairly important gene. But, glioblastoma cells are able to do without it because there is a closely related gene, ENO2, which can compensate for the loss of ENO1. The ENO2 gene also instructs cells to make the enolase protein (albeit a slightly different version), which is still able to metabolize sugar. Thus, as long as they have ENO2, the glioblastoma cells should be able to survive and thrive.

At least, they were able to survive and thrive before these scientists disrupted the ENO2 gene’s cellular activity. They used two separate approaches to target ENO2 in glioblastoma cells. In one experiment, they used a chemical inhibitor of the enolase protein to break its metabolic activity (the drug is called phonoacetohydroxamate, if you’re curious). In another experiment, they dampened the ENO2 gene’s ability to transmit its protein-synthesizing instructions to the glioblastoma cells. In both cases, the glioblastoma cells either slowed their rates of cell division substantially or stopped dividing altogether. Thus, the absence of ENO1 has primed these cancer cells to be vulnerable to inhibition of ENO2.

These findings are striking, and promising. However, a few caveats:

  • These experiments were not clinical trials.  They were conducted using glioblastoma cells grown in a laboratory, removed entirely from the complexities of the mammalian body.
  • The mechanisms used to target ENO2 have not been tested or perfected for use in patients.
  • Targeting the enolase protein will not cure cancer.  Not all cancer cell types shed the ENO1 gene.  In fact, there are glioblastoma cells that still have ENO1 (the authors of this study used them as controls in their experiments).

Let’s see what’s missing…

The true promise of this study has nothing to do with the ENO1 and ENO2 genes, phonoacetohydroxamate, or even glioblastoma.  The new hope here is that scientists can develop therapeutic methods to exploit the “collateral loss” of “passenger” genes in other types of cancer.  In this specific glioblastoma cell, it was the absence of sugar metabolism gene ENO1 which left it vulnerable to the inhibition of ENO2.  Other cancers have lost different sets of genes in their zeal to dump tumor suppressor genes.  Many of these “passenger” genes are known.  Their functions have been well characterized by biochemists, cell biologists, and molecular biologists over the past few decades (before we began to slash funding for research in the basic sciences).  Even though these have little to do with cancer, I suspect that many cancer biologists will be taking a new look at them in the hope that their absence can usher in a new bounty of cancer therapeutics.

It’s time to walk back that “HELL NO!!!”.

FURTHER READING:

Image credit: ALAMY

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About James Urton

I went to school to become a molecular biologist.  At some point in this long education, I discovered that I love communicating science to the general public: talks, writing, at a pub, on the street corner...  Whatever venue will let me hold your attention for a few moments.  Unfortunately, I can't do this for a living, since no one will pay me.  So, I have a job as a molecular biologist at the University of Washington, where I get to work with great scientists on some really awesome projects, and I'll blog about science here at Muller's Ratchet in my spare time. Why should the general public want to know anything about science? Here's my explanation (which also explains why I chose the name Muller's Ratchet for this site). Briefly as a graduate student (before I had to devote all of my time to graduating), I blogged at Adaptive Radiation.
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