Pain is universal, but cancer pain is particularly vicious. "Cancer patients have a bond that surpasses a healthy persons understanding," prostate cancer patient Cornelius Ryan, a prominent historian, wrote in his journal. "The presence of fear and the agony of pain are transmitted without words ... . My young friend [with lung cancer] wanted to die. [She] was being crucified by pain she could no longer endure. Now she is one more statistic."* The following year Ryan, in constant agony from bone metastases to his hips and legs, also died from his cancer.
While acknowledging the severity of cancer pain, doctorsuntil a few years agodid not view it as fundamentally different, in terms of neurophysiology, from other kinds of pain. Cancer pain was thought to be caused by the growing tumor mass compressing or infiltrating soft tissue, pressing on peripheral nerves, and sometimes cutting off blood flow to defined areas of tissue. But doctors and neuroscientists knew next to nothing about the molecular and biochemical sources of this cancer pain and had little to go on. Cancer pain seemed no different than ordinary pain, except in degree.
"Most clinicians and researchers failed to consider the basic mechanisms that underlie cancer pain," said University of Minnesota neuroscientist Alvin Beitz, Ph.D. The situation is now beginning to change as new knowledge of the mechanisms of cancer pain emerges. This work, in turn, is leading to a new generation of rationally designed painkillers.
Modeling Cancer Pain
Two mouse models of cancer pain developed in the late 1990s at the University of Minnesota started everything. In one model, cancer cells are injected into the leg of the mouse, and the injection hole is then plugged to prevent the growing tumor from escaping into soft tissue. The other model involves generating a tumor in the mouses foot and allowing tumors to spread to the surrounding soft tissue. Various neurochemical studies have been performed using both models with some striking and unexpected results.
Unlike other forms of pain, the number of astrocytes in the spinal cord rises dramatically in mouse models of cancer pain. Astrocytes are glial cells, one of the two main types of cells in the brain and spinal cord (the other being nerve cells, or neurons), and they perform a variety of nerve cell support functions.
In cancer pain models, "you get a tremendous number of [astrocytes]," said Beitz. "Then they communicate with one another and with nerve cells and really alter what the nerve cells are doing, and that probably leads in part to the development of chronic pain."
Cytokines, small messenger proteins secreted by astrocytes, are probably the immediate cause of the pain. Profound astrocyte proliferation is unique to cancer pain, and is probably one of the things that makes it so severe.
Another contributor to cancer pain is acidosis, the creation of an acidic environment around the tumor. Tumor cells have a pH around 6.8, as opposed to 7.4 for a normal cell, and this acidic environment can be painful in itself.
"Its thought that, when the tumor cells lyse, they can also stimulate acid-sensing ion channels," said University of Minnesota neuroscientist Patrick Mantyh, Ph.D. The opening of such ion channels electrically depolarizes neurons, causing them to fire and transmit pain signals.
From Bones to Brain
The pain is worst when cancer spreads to bone, as it often does in many common cancers. "Almost everybody whos dying of either breast cancer or prostate cancer has bone metastases," said Gregory Mundy, M.D., professor of cellular and structural biology at the University of Texas Health Science Center in San Antonio. As bone metastases spread, cells called osteoclasts break down bone tissue. (In prostate cancer this bone resorption occurs together with new bone formation.) Osteoclasts generate a highly acidic environment to degrade bone. The pH at the osteoclastbone interface is between 4 and 5, "a thousand times lower than what youll see in a normal cell," Mantyh pointed out, and this profound acidosis opens other ion channels, firing nerves and generating pain signals.
Visceral pain is another hallmark of cancer. It occurs, for example, when tumors cause a bowel obstruction or enlarge the liver capsule. "Visceral pain can be very disturbing to the patient," said Mantyh. "It has a real strong affective component." Neurosurgeons at the University of Texas Medical Branch in Galveston have shown that a separate pathway exists for the transmission of visceral pain from the spinal cord to the brain. But fuller knowledge of visceral pain mechanisms awaits the creation of a rodent model.
Neuropathic pain, pain caused by nerve damage, is also poorly understood in cancer. "Close to half of patients with advanced cancer and cancer pain have some form of neuropathic pain," said neurologist Paolo Manfredi, M.D., a pain specialist at the Memorial Sloan-Kettering Cancer Center in New York. Neuropathic pain in cancer patients is layered on top of the initial "tumorigenic" pain, caused by growth factors released by the tumor, and inflammatory pain, generated by the infiltration of inflammatory cells. "You really have three pains in one," said Mantyh. "Its probably why cancer pain is more difficult to treat."
The New Painkillers
But researchers are making progress in understanding the tumorigenic component, and this may soon lead to new pain treatments. In 1995, Joel Nelson, M.D., at Johns Hopkins Hospital in Baltimore, showed that prostate cancer cells secrete a peptide called endothelin-1. Three years later, neurologist Gudarz Davar, M.D., at Brigham and Womens Hospital in Boston, demonstrated that endothelin-1 caused pain in animals via endothelin-A receptors. Two years ago, Laura Eikmeier, a researcher in Beitzs laboratory, blocked pain in mice by injecting endothelin receptor antagonists directly into tumors, and Davar worked out the mechanism. "You block the endothelin-A receptor, you block the endothelin-1 signal," said Davar, who believes that this signal opens a sodium ion channel in nerve cells that leads to pain transmission.
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Other bone cancer treatments may be on the way based on newly identified molecular pathways. One reason so many tumors metastasize aggressively in bone is the presence of growth factors that stimulate their proliferation. Tumors "love to grow in bone marrowadore it," said Mundy. "Its like fertilizer to them." Tumors in bone, particularly in breast cancer, express parathyroid hormone-related peptide (PTHrP), which activates osteoclasts, perpetuating a vicious cycle of bone resorption and tumor growth.
But the cycle can be interrupted. For example, Chugai Pharmaceuticals has an anti-PTHrP antibody in phase III clinical trials for bone metastases, and Amgen is testing osteoprotegerin, a soluble receptor for RANK ligand, which is in early clinical trials. (RANK ligand signaling leads to osteoclast differentiation and activation.) Mantyhs laboratory was the first to show, in 2000, that osteoprotegerin reduced pain-related behavior in mice with bone tumors. Although bisphosponates, which inhibit osteoclast activity and have analgesic effects, have been on the market for more than a decade, osteoprotegerin is "probably more powerful," said Mundy.
An extremely popular, though completely unpublicized, experimental approach to treating pain in generalincluding cancer painis to directly target ion channels. Classic work in the 1950s by Alan Hodgkin, Sc.D., and Andrew Huxley, Sc.D., of Trinity College, Cambridge, demonstrated that the movement of ions through channels in the nerve cell membrane depolarizes the nerve cell and causes it to fire. This leads to the release of neurotransmitters at the nerve ending and impulse transmission to connecting nerve cells, and ultimately the brain. Pain is one such impulse, with neuropathic pain resulting from "ectopic," or abnormal, firing of neurons, leading to a constant state of neuronal hyperexcitability in the spinal cord or brain.
Recently, a series of these ion channels have been identified and cloned. Most relevant to cancer pain are the vanilloid receptors and the acid-sensing ion channel (ASIC) receptors. In 1997, David Julius, Ph.D., of the University of California at San Francisco, cloned the first vanilloid receptor, VR1. Although VR1 is the receptor for capsaicin, the main pungent ingredient in chili peppers, Julius and others quickly discovered that heat and acidity were also capable of opening the VR1 channel to ions, thus exciting nerves and generating pain. Around the same time, ASIC receptors were identified by researchers at the Centre National de la Recherche Scientifique in Valbonne, France.
Because the tumor environment is acidic, and acidosis contributes to cancer pain, VR1 receptor antagonists and ASIC antagonists could be extremely effective painkillers. "Pharmaceutical companies are actively developing drugs to target ... both of those ion channels," said Mantyh. Side effects, in theory, should be minimal, because these ion channels are mainly or exclusively found on specialized pain sensing neurons. "The expression pattern itself should limit potential side effects with this drug," said Mantyh. "Thats why theres such interest." Development is at an early stage, though, so drug companies are keeping their programs under wraps. But Mantyh knows of at least five companies already in the hunt for a VR1 receptor antagonist.
Morphine, first chemically extracted from the poppy plant in 1805, remains the principal drug for treating severe cancer pain. A new generation of treatments now seems on the verge of replacing, or at least augmenting, morphine and its derivatives. For bone pain, new drugs targeting endothelin-1, PTHrP, and osteoclast activity look promising.
And although the verdict will not be in for many years on ion channel inhibitors, their success would not only offer badly needed pain relief to cancer patients, but would validate the new molecular approach to pain. "Im not saying any of these is going to be the magic bullet," said Mantyh. But, he predicted, the molecular approach will eventually bear fruit, giving doctors "real power in designing new therapies to fit the individual."
NOTES
* From A Private Battle, by Cornelius Ryan and Kathryn Morgan Ryan. Simon & Schuster, 1979.
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