October 16, 2002
Genetic paradox provides new insight into cancer development
There is no molecular magic by which a normal cell suddenly turns cancerous. The process is, instead, a gradual one, as genetic mistakes (or mutations) accumulate in successive generations of cells until they become fully malignant.
As scientists are increasingly coming to realize, it is not just the mutations themselves, but the order in which they occur, that determines how a cell behaves and how aggressive it becomes.
New evidence for that idea came in a study published last month in the journal Nature by researchers at Dana-Farber and Brigham and Women's Hospital. Led by Nabeel Bardeesy, PhD, and Ronald DePinho, MD, of Medical Oncology, the investigators focused on a rare condition in hope of gaining new insights into the process of cancer development.
The condition, known as Peutz-Jeghers syndrome (PJS), has long posed a puzzle to scientists. Patients with the disorder develop an unusual array of problems: darkly pigmented spots on the lips or hands, benign (noncancerous) growths in the intestines, and malignant tumors of the pancreas, intestine, stomach, or breast later in life. A few years ago, researchers in Finland found that at least half of PJS patients have a mutation in a gene called LKB1. The paradox is how a single genetic error can be responsible for growths that remain benign and, at the same time, for malignant tumors in a variety of organs.
To resolve the question, the investigators developed a strain of mice with a mutation in the Lkb1 gene (the mouse equivalent of LKB1). As the mice aged, they developed benign growths, called polyps, in the stomach and intestines, much as people with PJS do.
The resemblance suggested the mice would be useful for understanding the human disease.
"Our next question was, 'How does the loss of the normal LKB1 protein cause cells to grow abnormally?'" explains Bardeesy, the study's lead author. He and his colleagues focused on cells called mouse embryonic fibroblasts (MEFs) that are often used for studying the characteristics of cancer. They gathered MEFs from the mutant mice, grew laboratory samples of the cells, and compared them to cells from normal mice.
The differences they found were partly predictable and partly startling.
When normal cells are collected in a laboratory dish, they grow for a while and then stop. This happens because they're able to sense abnormalities in their environment. Cells that lack LKB1, however, ignore the stop signal and continue to grow and divide. In this respect, they share an important characteristic with cancer cells, which continue to divide long past the point when their internal clock tells them to stop. Cells that fail to die on schedule are termed "immortal."
"This aspect of our findings wasn't surprising," Bardeesy remarks. "It suggests that LKB1 normally helps limit cell growth. When LKB1 is lost, cells become immortal, which is one step toward cancer."
A matter of timing
The results of a second experiment were more unexpected. When cancer-causing genes called oncogenes are inserted into normal cells, they're transformed into cancer cells that grow very rapidly. When oncogenes were added to the LKB1-deprived cells, however, they didn't become cancerous.
"At first, the results seem contradictory," Bardeesy notes. "LKB1 mutations remove the normal brakes on cell growth, but they also block the cancer-promoting action of oncogenes. They seem to make cells both more and less susceptible to becoming cancerous."
The solution has to do with the timing of the mutations — at what point they occur on the trail of molecular mishaps in a cell's odyssey from normalcy to malignancy.
"We hypothesize that when an LKB1 mutation occurs in normal cells, the cells grow irregularly but become resistant to further cancer-causing changes," comments senior author DePinho. "The fact that people with PJS develop benign polyps — which don't progress to cancer — supports this idea."
"At the same time, we know that PJS patients develop malignant tumors — of the breast, colon, and pancreas — at a very high rate," he continues. "It's possible that when LKB1 mutations occur in cells that are already on the road to cancer, they push the cells further into an abnormal, fast-growing state."
Bardeesy, DePinho, and their colleagues plan further experiments to confirm these hypotheses and study the impact of the LKB1 protein on surrounding cells.
Co-authors of the study, which ran in the Sept. 12 issue of Nature, include Nathaniel Hathaway, Aram Hezel, MD, Massimo Loda, MD, Norman Sharpless, MD, Sabina Signoretti, MD, and Manisha Sinha, of Medical Oncology, and Daniel Carrasco, MD, PhD, of Brigham and Women's Hospital.
This story first appeared in the Oct. 16, 2002 issue of Inside the Institute.
