The complexity of cancer

About a week ago, there appeared a story in the New York Times about recent discoveries in cancer research written by George Johnson and entitled Cancer’s Secrets Come Into Sharper Focus. Overall, it was a better-than-average article for the lay press about recent discoveries in cancer research that go beyond just the cancer cell and just oncogenes. I must admit, however, that certain aspects of it irritated me, not the least of which is that it appeared to buy into one of the most cliched of tropes about medicine and science in spinning the story along the lines of “everything you know about cancer is wrong.” More pettily, the author couldn’t resist a dig at the scientists and physicians at the meeting described as “fueled by the free espresso offered by pharmaceutical companies hawking their wares.” In retrospect, I regret not having blogged the article at the time it was released, because it didn’t take long for purveyors of quackery to leap at it and use its contents to try to argue that scientists don’t understand cancer. While it may be true that we have a long way to go before we truly “understand” cancer, it is even more true that quacks don’t understand cancer at all; indeed, many of them cling to a false understanding of cancer.

Unfortunately, Johnson’s article has been used as the basis of an argument that, because our understanding of cancer has changed significantly over the last decade, “conventional” scientists don’t understand cancer, the implication being that the quacks do. Today, in part I of what will be a two-part post, I’ll discuss the NYT article, its good, its bad, and its indifferent, hopefully in the process illuminating how complex cancer is. Tomorrow or Thursday, I’ll lay some not-so-Respectful Insolence on a quack who uses this article as a jumping off point to argue for cancer quackery, particularly his hilarious criticisms of the article’s “shortcomings.”

I’ll begin by showing you a bit why the NYT article leaves itself open to that such unfortunate uses:

For the last decade cancer research has been guided by a common vision of how a single cell, outcompeting its neighbors, evolves into a malignant tumor.

Through a series of random mutations, genes that encourage cellular division are pushed into overdrive, while genes that normally send growth-restraining signals are taken offline.

With the accelerator floored and the brake lines cut, the cell and its progeny are free to rapidly multiply. More mutations accumulate, allowing the cancer cells to elude other safeguards and to invade neighboring tissue and metastasize.

These basic principles — laid out 11 years ago in a landmark paper, “The Hallmarks of Cancer,” by Douglas Hanahan and Robert A. Weinberg, and revisited in a follow-up article this year — still serve as the reigning paradigm, a kind of Big Bang theory for the field.

But recent discoveries have been complicating the picture with tangles of new detail. Cancer appears to be even more willful and calculating than previously imagined.

This is, unfortunately, a massive straw man. Yes, it is true that in the past science focused almost exclusively on the cancer cell and the mutations that drove it to become cancerous. However, contrary to what is portrayed in Johnson’s article, the understanding that cancer is about more than just the cancer cell began long before ten years ago. In fact, you can see evidence of that in the classic article (published, intentionally no doubt, at the turn of the millennia) that is mentioned in the passage above. Right there in the article is a figure that I personally have used in many talks to point out that cancer is not just about the cancer cells. Here is Figure 3:

Notice something? On the left is the “old” view of cancer (the “old view” eleven years ago). This old view considers mainly the cancer cells and views tumors as primarily collection of cancer cells. This is contrasted to the figure on the right, which portrays a tumor as a complex tissue containing many cell types. To emphasize how little Johnson apparently understood Hanahan and Weinberg’s classic paper, here’s what the caption to this figure in Hanahan and Weinberg’s classic paper says:

The field of cancer research has largely been guided by a reductionist focus on cancer cells and the genes within them (left panel)–a focus that has produced an extraordinary body of knowledge. Looking forward in time, we believe that important new inroads will come from regarding tumors as complex tissues in which mutant cancer cells have conscripted and subverted normal cell types to serve as active collaborators in their neoplastic agenda (right panel). The interactions between the genetically altered malignant cells and these supporting coconspirators will prove critical to understanding cancer pathogenesis and to the development of novel, effective therapies.

In other words, the paper that Johnson cites as evidence of how scientists clung to a simplistic model of how cancer operates eleven years ago is anything but that. Rather, it pointed out that the discoveries of the decade before (i.e., the 1990s) had complicated our previous seemingly neat understanding of cancer. Well, it wasn’t that our understanding of cancer was so “neat”; rather, it was that our understanding back then was indeed primarily focused on the cancer cell. However, contrary to what Johnson implies, that hasn’t been the case in over 10 years. It is, however, a convenient narrative to make it seem as though the discoveries described in Johnson’s article are so utterly novel that they were not the active topic of study far longer than ten years ago. Indeed, when I was in graduate school, I studied the tumor microevironment, specifically tumor angiogenesis, starting in 1996, five years before. When Johnson says that “research is increasingly focused on the fact that a tumor is not a homogeneous mass of cancer cells” but “also contains healthy cells that have been conscripted into the cause,” he should look at the eleven year old article that he cites, which says more or less the same thing. In other words, this is not new news, nor is it new for tumors to be compared to “renegade organs sprouting inside the body.” The tumor microevironment has been a fertile area for cancer research at least as long as I can remember, which in terms of my interest in cancer biology is at least 20 years.

In all fairness I’ll point out that Johnson isn’t wrong about some things. Rather, it’s the emphasis that irritates me because it makes discoveries that are not particularly new seem new. One exception is a discovery whose consequences Hanahan and Weinberg could scarcely have envisioned in 2000, namely the discovery of microRNAs. microRNAs are small RNA molecules that are able to bind to messenger RNA and prevent its translation into protein or induce its degradation, a process known as gene silencing. Given that microRNAs were only discovered in 1998, the importance of microRNAs in cancer biology is truly a new discovery that has emerged out of the last decade or so. In doing so, our increasing understanding of micrRNAs has rocked our understanding of cancer and many other cellular processes. Ten years ago, no one could have suspected how important microRNAs are in regulating gene expression. Indeed, a single micrRNA (miRNA for short) can regulate hundreds, even thousands of messenger RNAS (mRNAs), which are the RNAs that are used as the template that translates the information in the genome into protein. So ubiquitous have miRNAs become in cancer research that yours truly has even gotten into the act, having found one miR that might be important in indirectly silencing the expression of the tumor suppressor gene TP53. More recently, it turns out that miRNAs can be detected in the serum and that serum miRNA profiles might actually serve as biomarkers for cancer and other diseases.

But it goes beyond even that. There’s more to other genomic contributions to cancer than miRNAs. Indeed, we now refer to a whole class of RNAs as “noncoding” RNAs (ncRNAs) with regulatory functions that we haven’t yet figured out. However, next generation sequencing techniques, coupled with huge increases in computational power and the development of new algorithms that allow the analysis of petabytes of data, have led to this new knowledge, even to the ability to sequence the genome of individual cancers at a cost that is falling to ranges that are not astronomical. Remember, all of this has discovered over the last twelve years or so. The last decade in cancer research has been truly amazing. The next decade will be even more exciting, as scientists try to sift through this incredible mass fo data and as rapid declines in the cost of next generation sequencing techniques make sequencing the genomes of individual cancers feasible.

I just wish Johnson hadn’t fallen for the “junk DNA” trap:

Most DNA, for example, was long considered junk — a netherworld of detritus that had no important role in cancer or anything else. Only about 2 percent of the human genome carries the code for making enzymes and other proteins, the cogs and scaffolding of the machinery that a cancer cell turns to its own devices.

These days “junk” DNA is referred to more respectfully as “noncoding” DNA, and researchers are finding clues that “pseudogenes” lurking within this dark region may play a role in cancer.

Of course, the issue of “junk DNA” is a lot more complicated than that, and Johnson’s passage sounds uncomfortably like creationists gloating every time scientists find some ncRNA or other that has a previously unsuspected function. As Larry Moran points out, “noncoding” has traditionally meant “does not make protein” and has never meant “has no function.” Indeed, even in 1972, it was known that there were forms of RNA with functions other than making protein, such as transfer RNAs (tRNAs transfer amino acids to the ribosomal complex as protein is being translated), ribosomal RNA (rRNA), and regulatory regions in promoters. In brief, “junk DNA is not the same thing as “noncoding DNA” and never has been. Moreover, even the discovery of miRNAs and other forms of ncRNAs with gene regulatory functions does not imply that cancer scientists ignored “junk DNA” all these years. But it makes a great hook to portray scientists in the past as having been “obsessively focusing their attention on 2% of the genome.”

Don’t get me wrong. There is much to like in Johnson’s article, such as the discussion of how microbes might contribute to the development and growth of cancer and the explanation of how miRNAs have become major players in understanding cancer. Johnson also gives a great summary of the complexity of cancer in his final paragraph:

With so many phenomena in search of a biological explanation, “Hallmarks of Cancer: The Next Generation” may conceivably be followed by a second sequel — with twists as unexpected as those in the old “Star Trek” shows. The enemy inside us is every bit as formidable as imagined invaders from beyond. Learning to outwit it is leading science deep into the universe of the living cell.

As I’ve pointed out before, cancer is really, really, really complex. I wrote about this at length six months ago and still recommend that, if you haven’t already, you go back and read that post. It’s one of my better ones, if I do say so myself, and it makes an incredibly important point, although in retrospect I realize that I actually did concentrate mainly on the cancer cell and its genetic derangements. In actuality, the complexity of cancer goes far beyond the genome. There are metabolic derangements (for example, the Warburg effect); complex interactions between cancer cells and the tumor microenvironment, between cancer cells and the tumor vasculature, and between cancer cells and the immune system; there are levels upon levels of genetic derangements, ranging from chromosomal rearrangements, to single mutations, to alterations in microRNA expression; and lots and lots of abnormal intracellular signaling. Although we’ve made great strides in starting to understand the the abnormal “wiring” of the cell and how abnormal interactions of cancer cells with their surrounding “normal” tissue environment contribute to its malignant behavior, we do not as yet have a good handle on what determines how this process proceeds and, more importantly, how to intervene effectively in such as way that doesn’t cause significant “collateral damage,” as chemotherapy, radiation therapy, and surgery can. Add to that the fact that cancer is not a single disease, but rather hundreds of different diseases in which normal cells lose their normal checks and balances and in essence parasitize the body, each with potentially different biology (sometimes radically so) and requiring different approaches to treatment, and it is more understandable that even forty years of the “war on cancer” is only enough to begin to scratch the surface.

Unfortunately, that doesn’t stop the quacks from using gaps in the scientific understanding of cancer as openings to sell their quackery.