The theme of the Keystone conference was “Genes Dogs and Cancer”. A diverse group of dog owners, breeders, practicing veterinarians and research scientists in genetics and molecular biology gathered in Colorado in late May 2001. The goals were to foster new collaborations between researchers and practicing veterinarians, identify multi-generational high-risk cancer pedigrees, present new research findings from the laboratories and clinical trials and new state-of-the-art research methods to advance canine cancer research. Several dog owner/breeders were given a chance to present to the scientists their personal experiences with the tragedy of early heritable canine cancer deaths, putting a vivid face on the disease as we shared their sorrow and frustration.
Cancer is not a single disease. It is many diseases in a progression along a continuum from a normal healthy cell to widespread malignancy. There are more than one hundred distinct types of cancer and there are further variations on these types. There will be no single silver bullet that “cures” cancer but recent advances in the understanding of cancer suggest that we are on the verge of a paradigm shift in how cancer is understood and intervention planned.
The genetic control of cell growth, cell death and DNA repair is being examined and maps of detailed signaling pathways of this control are being drawn. A large body of research suggests that cancer develops in a Darwinian fashion from a series of heritable, spontaneous, or environmentally induced genetic mutations or combination thereof. An early step in this evolutionary process is the the development of the “mutator phenotype”, as described by keynote speaker, Dr. Lawrence Loeb. This change prevents the body from repairing or removing mutations. Cancer cells have many mutations, sometimes thousands, and selection for a mutation that allows the cancer to bypass the body’s defenses against these sudden genetic changes speeds its development. The genome of the cell becomes unstable and this instability allows further mutations to change the cell from healthy to precancerous to cancer. The first enemy over the wall disarms the guards and opens the doors to his cohorts or, in the case of an inherited mutator phenotype, the disarming is done by a native traitor.
Drs. Hanahan and Weinberg suggest in an article in Cell in 2000 that there are six essential alterations that most if not all cancer cells must acquire to collectively dictate malignancy. The first is the ability to grow without a signal from outside the cell to move from a quiet to proliferating state. Normal cells require an outside signal but cancer cells become self-sufficient. They need not wait for someone to tell them to grow. Researchers have been able to describe dominant oncogenes (genes which initiate cancerous changes) that target this ability to become self-sufficient.
Second, the ability to avoid anti-growth signals: the healthy body has signals that control overgrowth by telling actively dividing cells to go into a quiet phase or to develop further into a cell type that cannot reproduce further when appropriate. Cancer cells must circumvent these control mechanisms if they are to grow malignantly.
A third mechanism is that cancer cells must be able to evade the healthy body’s signals for an abnormal cell to commit suicide… a mechanism called apoptosis. Many heritable cancers have mutations in the normal control mechanisms for signaling apoptosis, e.g. colon cancer in humans. Researchers are targeting pathways that would turn back on this programmed cell suicide and kill cancer via apoptosis.
Normal cells can divide just 60-70 times until they exhaust their ability to reproduce. A fourth acquired mechanism of cancer cells is the ability replicate limitlessly. At the Keystone conference, Dr. Barbara Kitchell described how her laboratory was using dogs with tumors as a model for methods of inhibiting telomerase, an enzyme that has been found to trigger the most common method by which cancer cells become immortal.
Cancer cells need a food supply to grow. Without blood vessels to provide oxygen and nutrients, tumors could grow to only a very small size. The fifth acquired trait is the ability to call for the growth of new blood vessels or angiogenesis. There are several cancer treatments in late stage clinical testing that target angiogenesis and cut cancer off from its fuel supply.
And ultimately, the sixth trait needed by cancer cells is that they must be able to invade nearby healthy tissues and spread elsewhere in the body. They conscript healthy cells and alter themselves or their nearby environments so that they can flourish. It is this that most commonly leads to the death of the patient from cancer.
Cancer develops over time and in many cases offers opportunities for early detection, prevention and interference with development of the above needed traits. Research is targeting the above pathways for new methods of halting cancer’s progression.
Researchers at the Keystone conference described the mapping of cancer susceptibility genes in dogs and how oncogenes and tumor suppressor genes may be sporadic or heritable and how their presence or absence might someday be used to predict response to conventional therapies and survival times. The mutations in proto-oncogene c-kit have been identified in several malignant mast cell cancer lines by scientists sponsored by the CSPCA Charitable Trust and have been associated with more aggressive mast cell cancer. Dr. Roy Levine described how the PTEN tumor suppressor gene was mutated or down-regulated in a high percentage of canine osteosarcoma cell lines and tumors. Dr. Brewer presented data that lowering a patient’s copper levels could be used to control angiogenesis by cancer cells. Recurrent chromosomal aberrations in canine lymphoma were described by Dr. Rachael Thomas and others described genetic determinants of metastasis in canine osteosarcoma (70-80% of dogs with osteosarcoma die from the metastases despite early elimination of the primary tumor). Plans for genetic mapping of familial canine cancer susceptibility genes were discussed.
The conference offered an opportunity to peek at how far we have come in understanding cancer and how scientists continue to unravel its mysteries. As we mature in our understanding of this disease, I have great hope that we will be able to offer all cancer patients earlier detection and less toxic, more health-building treatments. Dr. Loeb emphasized how even now, a person that takes known preventive actions can vastly increase the probability that cancer will not occur in his or her natural lifetime. Our canine friends are benefiting from serving as animal models for human cancer (and the reverse, as humans serve as models for our canine cancer treatment protocols) in a powerful synergism. I am very grateful to the CSPCA Charitable Trust for the opportunity to take part in this conference.