Pets don't die from cancer. They die from complications arising from the expansion and spread of the cancer. It is how cancer affects the lungs, liver, kidney, brain and gut that leads to the demise of the patient.
What Is Metastasis?
Metastasis occurs when the primary tumor spreads to other parts of the body. Some cancer cells break off from the tumor, travel through the bloodstream or lymphatic system to other parts of the body then multiply. And before traveling to distant sites in the body, cancer cells may also spread to the lymph nodes near the tumor.
Cancer cells often end up in the liver and lungs because those are the first places that the blood passes through on its way back to the heart. If the cancer cells are not trapped by the capillaries in the liver and lungs, they will flow back to the heart and out into other organs such as bone, kidneys, brain and skin.
In these organs, there is an abundant blood supply with lots of nutrients and growth factors, making it a fertile place for tumor cells to grow. So it's a seed-and-soil situation. The malignant cells can land anywhere but they're more likely to grow if they are in an area that's conducive to growth.
Oncologists talk often about the significance of micrometastases, a cluster of small-sized cancer cells that have yet to form a vascular supply and cannot be recognized from adjacent normal cells in most circumstances unless special stains are applied (immunohistochemical methods, for example).
Scientists know a great deal about how tumors originate and develop, but relatively little about how cancer manages to metastasize and invade distant tissues and organs.
Metastasis is a highly inefficient, multi-step process that requires cancer cells to jump through many hoops. The entire operation involves so many steps that it raises an obvious question: How do cancer cells acquire the ability to do all this?
According to a study reported in the journal Cell (June 2004), they don't. Rather, they hijack an existing cellular process and use it to disperse themselves throughout the body.
Apparently the tumor cell misappropriates a protein called Twist. Twist is a gene regulator, meaning that it tells genes when to turn on and off. But Twist is mainly active in early embryonic development, where it enables cells to move from one part of an embryo to another and allocate these cells into different tissues.
As an embryo develops, Twist's functions are no longer necessary, and it soon becomes dormant in most tissues throughout the rest of an organism's life. But through a process that still is unclear to researchers, tumor cells reactivate this long-dormant protein and acquire the ability to move throughout the body.
Twist appears to be active only in metastatic cells. It causes cells to separate from one another and lose cell-to-cell adhesion, allowing them to travel. If the gene is disabled, the process is arrested.
Although clinical applications of research performed in mice remains unclear, the potential for developing a Twist inhibitor, a drug that wouldn't kill a tumor but rather stop its metastatic capabilities, is exciting.
Likewise, there are diagnostic and prognostic possibilities, knowing if the tumor has the potential to metastasize by identifying the expression of the Twist gene, or like gene, products following removal of the primary tumor.
… And the 'Soil'
The endothelial lining of our vessels contain recognition proteins called integrins. Various researchers have shown that tumor cells preferentially attach to beta-3 form of the alpha-2:beta-3 integrins found commonly along the vasculature in many tissues such as the liver, lungs and bone.
In a study reported in the Proceedings of the National Academy of Sciences (November 2003), osteosarcoma cells that were genetically engineered with a defect in recognizing the beta-3 form of vascular integrins failed to produce metastatic lesions when injected into mice.
Interestingly, this same group found that platelets, upon aggregation, over express the beta-3 form and augment the spread of tumor cells. It is known that human beings with metastatic cancer frequently have high platelet counts and excessive blood-clotting activity.
When mice were treated with a drug that blocked the formation of the beta-3 form found on platelets and injected with osteosarcoma cells, they had fewer and smaller metastases. While there are several hypotheses for how platelets may help tumor cells metastasize, most theories assume that platelets bind to tumor cells circulating in the bloodstream and begin to bind to other platelets, gathering tumor cells together.
The platelets may hide tumor cells from the immune system, supply them with essential growth factors or just provide them with a ride.
Does this work suggest that a potent blocker of platelet function, such as aspirin, will reduce the risk of metastasis? Likely not. In the mouse studies, the dosage of aspirin required to block the beta-3 form caused profuse bleeding.
Kevin A. Hahn, DVM, Ph.D., Dipl. ACVIM (Oncology), is director of Oncology Services at Gulf Coast Veterinary Specialists, Houston (www.gcvs.com/oncology), and is the oncology consultant for YourNetVet (www.yournetvet.com).