8 December 1998 CapCure5\Reed.MS-- 850 words
Apoptosis is critical path to cancer;
bcl-2, other therapeutic targets emerge
Lake Tahoe, NV--Cancer is an imbalance between the cell's accelerator and brakes, the biologists often say here at CapCURE'S 5th Annual Scientific Retreat.
John C. Reed, MD, PhD, is trying to fix the brakes. Apoptosis curbs cancer by monitoring the function of cells, and killing them when they run out of control. Why does apoptosis fail, and how can we restore it?
"The goal is to understand why programmed cell death fails to occur in prostate cancer," said Dr. Reed, who is scientific director and professor at The Burnham Institute, La Jolla, CA. "And we're trying to elucidate the mechanisms that may contribute to that."
"Once we've identified those mechanisms we can then do experiments to understand how important those mechanisms are in the big picture," said Dr. Reed, who reviewed these mechanisms at the Retreat this September.
"Our lab has identified a number of roadblocks to apoptosis: defects in the steroid hormone pathway, mitochondrial-dependent steps, the upstream path, the downstream path, and kinases," said Dr. Reed. "With a better understanding of these steps, we can disturb the homeostatic balance and overcome apoptosis resistance."
One of the most clinically important roadblocks to apoptosis is Bcl-2. When Bcl-2 is overproduced, it protects the cell from apoptosis, but that protection can be overcome in the test tube. "We can ablate the function of that gene as an experiment," said Dr. Reed.
"How important is that gene to the prostate cancer cell?" asked Dr. Reed. "If we could wave a magic wand to eliminate the Bcl-2, what would happen? are there other redundant mechanisms that would still allow the cell to survive?"
"The gratifying thing," said Dr. Reed, "is that although we can see a number of potential points that are in the pathway that can be blocked, we have identified some steps that seem to be critical. If we knock out some of the critical genes, bcl-2 being an example, this can have a major effect on the survival of the cells."
"The challenge is to find out which are the critical ones," said Dr. Reed.
"Ablating the expression of a single gene like bcl-2 sometimes makes a big difference in the survival of the cells or their sensitivity to chemotherapy drugs," said Dr. Reed.
"Different roadblocks to apoptosis may be more important in early vs late stage tumors," said Dr. Reed. "So we have to sort out some of the heterogeneity of cancer. There's probably more than one pathway to prostate cancer and we have to recognize that molecular heterogeneity."
"For example, about half of hormone refractory cancers express bcl-2," said Dr. Reed. "Those patients would be candidates for bcl-2 anti-sense therapy. You have to give the right therapy to the right patient." Cancer therapy will be more like microbial therapy, he said (a repeated theme at the CapCURE conference). "You will send it to the lab" to find out its sensitivity, he said.
"We're particularly interested in apoptosis," said Dr. Reed, "because the only good tumor cell is a dead tumor cell."
"We don't want to just stop them from dividing or migrating or growing a blood supply," said Dr. Reed. "The genetic instability in tumor means that if you don't kill them, they're going to find a way around almost any therapy."
Activating the immune system will not overcome an apoptosis defect, said Dr. Reed. All the immune system does is activate the programmed death pathway, he explained. "So if you have a defect in the programmed death mechanism, the immune system isn't going to be able to kill it anyway."
Quite a few details have been worked out, said Dr. Reed. Androgen independence "is one of the manifestations of a defect in the cell death pathway," he said. "Overexpression of bcl-2 seems to be one of the major defects," and confers resistance to a very broad spectrum of apoptotic stimuli: radiation, chemotherapy, the immune system, hypoxia. "It allows them to survive in a suspended state so that they can circulate around for metastasis. It allows cells to tolerate genetic instability, to block p53." (p53 is the classic tumor suppressor gene, which monitors cell division and stops it, and kills the cell if necessary, when it detects abnormalities.)
"Bcl-2 is a multi-functional protein," said Dr. Reed. "One of its functions involves controlling mitochondria, and protecting them from stimuli that damage the cells." That includes chemotheraputic drugs, which induce mitochondria to loss of electron exchange transport.
"Cell death is under active suppression all the time," said Dr. Reed. "The basal cells of the prostate normally express Bcl-2. Those are long-lived cells that don't require testosterone for survival. They're stem cells. They express bcl-2 when they differentiate to the epithelial secretory cells of the prostate." The epithelial secretary cells don't express bcl-2. They are short-lived cells, he said. "And they are hormone dependent."
"By delineating some of these steps," said Dr. Reed, "we can design strategies to overcome apoptosis resistance."