In the 1980s, many cancer researchers took what seemed like a logical leap of faith: If several genes must be mutated over time to create a tumor cell, it must follow that the first gene to be mutated acts as the initial flashpoint in starting a tumor. Find the flashpoint; pinpoint the cause of the tumor.
But, what if tumor cells in some parts of the body do not have a single flashpoint? What if they have multiple flashpoints that erupt over time into raging tumors that are highly metastatic, largely resistant to chemotherapy, and extremely deadly?
That is the scenario that now faces molecular biologists and geneticists who study pancreatic adenocarcinoma, which accounts for about 90% of cancer in the pancreas. After an intensive, decade-long search to locate a tumor-initiating gene, many scientists say they now have doubts that such a thing exists. With this doubt has come the growing realization that their hard work likely will yield no quick answers for patients.
This has placed researchers in a delicate position as they head into the new millenium. Knowing just how deadly pancreatic adenocarcinoma is its incidence and mortality rates are nearly the same they must continue to hold out hope that a miracle gene will emerge from their studies and clear the way for immediate diagnostic and treatment advances.
And yet, scientists also say that chance discoveries will no longer suffice. Having already bagged numerous other genes and proteins involved in the disease, many say they feel compelled to take the next and more laborious step of working out the molecular wiring, or pathways, inside a pancreatic tumor cell. They say only by defining the very pathways that tumor cells employ to grow or thwart cancer drugs will doctors have their best shot at dramatically improving patient survival.
Empty Cupboard
Less than 10 years ago, most molecular biologists viewed pancreatic cancer like a chef would an empty cupboard. Tumor samples were often hard to find, cell lines were sparse, and animal models were generally inadequate.
Moreover, many scientists believed the cure to pancreatic cancer would be found by studying hormones not genetics or cell biology.
"Everyone was convinced that because hormones played such a dominant role in regulating secretion in certain pancreatic cells, they must be playing a dominant role in tumor development," said Charles Ulrich II, M.D., of the University of Cincinnati Medical Center.
By the mid-1980s, this thinking slowly began to shift. Much of the impetus came from the work of Henry Lynch, M.D. and colleagues at the Creighton University School of Medicine in Omaha, Neb., who had identified several families with histories of pancreatic cancer. More scientists began to say that if this hereditary link was correct, there had to be a gene for pancreatic cancer stitched somewhere into the human genome, an idea that to date has not panned out.
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One was a team of researchers at Johns Hopkins University in Baltimore led by Ralph Hruban, M.D., and Scott Kern, M.D. "Our original thoughts were that we had two possibilities," said Kern. "Either there really weren't that many genetic changes in pancreatic cancer and that explained why there was a low number of reported changes. Or, nobody had simply looked at it. In fact, it was probably the latter."
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What Kern and his colleagues around the world have produced, largely over the last 5 years, is one of the more detailed working models of tumor development in cancer research. The process begins with changes in a thin layer of epithelial cells that line the pancreatic ducts, a network of tubes that supply a heavy flow of digestive juices to the intestine. For whatever reason, these cells can grow abnormally long and narrow, resulting in flat hyperplasia. If the abnormality worsens over time, the cells will become increasingly crowded and disordered, called papillary hyperplasia, possibly giving rise to a tumor and cancer.
Like a benign polyp in the colon, scientists say flat hyperplasia represents a first step on the road to cancer. But, as in the colon, one step does not an entire journey make. Studies suggest that although about half of all people will develop flat hyperplasias by their later years, fewer than 10% of the population will take the next step to papillary hyperplasia. In fact, researchers estimate that only about one in 500 ductal lesions has a chance of completing the journey to cancer.
They also estimate that to progress to cancer, a duct cell must acquire at least 25 different mutations. As scientists have discovered, these mutations are in many cases highly selective for certain genes. For example, the K-ras proto-oncogene is altered in about 90% of pancreatic cancers, making it the most commonly mutated gene known in any type of tumor. Likewise, the cell-cycle-inhibitor gene p16 is knocked out in about 40% of tumors, the multi-tasked p53 is knocked out in half to three-fourths of tumors, and the DPC4 gene is inactivated in about 30% of tumors.
And yet, none fit the bill of gatekeeper gene. K-ras, for instance, has been found to be altered in about half of cells with flat hyperplasia, meaning the other 50% do not need to upregulate this oncogene to become cancerous.
Murray Korc, M.D., a scientist at the University of California at Irvine who has played a key role in studying growth factors and their receptors in pancreatic cancer, said he thinks it is too preliminary to make a determination one way or the other. "There may well be some sort of gatekeeper gene that allows the cancer cells to acquire all of these types of hits [mutations]," he said. "At this point, we don't know enough."
No "Gatekeeper"
But some say the evidence is mounting against a gatekeeper. One reason is gatekeeper genes typically open the door for the formation of numerous precancerous lesions. In the colon, for example, the presumed gatekeeper, APC, clears the way for multiple benign polyps when it is inactivated.
That is not the case in the pancreas. In fact, tumor cells from the pancreas and colon have somewhat distinct molecular profiles, an indication that they exploit different growth systems. While the APC gene is considered the tumor-initiating, or "gatekeeper," gene in colon cancer, it is rarely mutated in pancreatic adenocarcinoma. Neither is beta-catenin, another frequently mutated gene in the colon. Conversely, K-ras is mutated in only about half of colon cancers, with most mutations occurring in a part of the gene that is rarely affected in pancreatic cancer.
Kern hypothesized that perhaps the pancreas simply could not afford to employ a gatekeeper system to control its growth. "In the colon, you pay a little price for having a gatekeeper system," he said. "Inactivation of only one gene [APC] gives you a neoplasm. If you did that in the pancreas, you'd have a possibility of occluding a duct. This is probably one of the worst scenarios for the pancreas. So, the colon can have a system that is a little looser, while the pancreas may have to set up a more complex system."
Another strike against a pancreatic gatekeeper, Kern said, is he and his colleagues may have already found all of the high-frequency genes that are to be had. If so, he said, the field could face the unenviable task of spending much more of its time searching for myriad low-frequency genes, mutated in 1% or 2% of cancers, without the availability of research tools that are sensitive enough to find them, particularly in families.
Chess Match
Using the analogy of a chess match, Kern said, "This is a funny game of chess in which the king and queen, the high-frequency genes, are sitting out front on the board, and we've picked them off. But the pawns are hidden all over the place. Each one playing a small role, but yet they are there. To understand your enemy on the board, you're going to have to find them."
According to most scientists, they also will need to understand much more about the actual signaling pathways that pancreatic tumor cells exploit to survive. While assembling the proteins involved in key signaling pathways will be a common theme throughout cancer research, they say the need is particulary acute in the pancreas.
To a degree not seen in other cancers, pancreatic adenocarcinomas literally shut themselves off to the outside world. They typically have knocked out their TGF-beta growth inhibition system; inactivated the pathways that trigger programmed cell death, a common target of cancer drugs; and silenced proteins needed to control multiple levels of the cell cycle.
"The combination results in an autocrine [self-induced] overdrive phenomenon that can't really be effectively shut down," said Ulrich. "The tumor has so many ways of dealing with you trying to kill it, that they are very refractory to chemotherapy."
How intimately will they need to understand the cell's internal molecular wiring? According to some scientists, the task might be as straightforward, a relative term in pancreatic cancer, as learning to reconstitute the cell death pathways, then targeting them with drugs. But with few clues available to explain why programmed cell death does not work in pancreatic tumors, this could turn out to be a tall order in the short term.
Ulrich said he thinks treatment advances will not be as simple as mastering one pathway. He said the field will need to understand the so-called secondary messengers, the numerous back up systems that pancreatic tumor cells employ whenever needed to thwart the thrust of cancer treatments.
"If you try to hit these cells at the level of the receptor, there is so much redundancy in the tumor cells that you're not going to be effective," Ulrich said. "You need to define a common set of messengers and a common set of second messengers that modulate them. Once you've done that, I think that you have at least an intelligent strategy towards going after the tumors."
Still, after so many lean years, scientists say they are cautiously optimistic about the future.
"It is amazing some of the things that we can now do in the test tube to these cancer cells. I think as the technology improves, and even with the knowledge that we already have, things are going to change [for the better]," said Korc. "I think there is going to be a lot more progress."
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