FEATURE ARTICLE
Metastasis
The spread of cancer cells to distant sites implies a complex series of cellular abnormalities caused, in part, by genetic aberrations
Cornelis J. Van Noorden, Linda Meade-Tollin, Fred Bosman
Fighting Cancer and Its Spread
It is the fondest wish of all scientists who study cancer that it can be defeated. Scientists ardently hope to find some very precise way to curtail cancer's unrestrained growth without harming healthy cells, an advance that would represent a vast improvement over therapies currently available.
Right now, when cancer is diagnosed, the tumor is often removed surgically. But there is always the possibility that some cancer cells remain at the original site, and that others may have already started to migrate to distant organs. So the patient is given radiation, which can eradicate cells by apoptosis. Radiation can be applied very specifically to sites in the body where the primary tumor was located in order to destroy any remaining cancer cells. But if undetected metastases are present elsewhere in the body, they go untreated.
For this reason, radiation is often given in conjunction with chemotherapy. The chemicals used in chemotherapy are almost all designed to curtail division and proliferation. The rationale is that cancer cells are dividing more rapidly than other cells in the body and are therefore most vulnerable to the effects of the chemotherapeutic agents. However, chemotherapy is quite a blunt weapon, and many normal cells with high turnover rates, such as skin, hair and blood cells, are affected along with the cancer cells. Sometimes cancer cells develop resistance to chemotherapy and become insensitive to its effects. Once that happens, the cell actually pumps out drug molecules, leaving itself and its progeny unharmed. Scientists therefore hope to target aspects of cancer cells that are different from healthy cells in order to develop drugs and therapies that attack the cancer cells only.
In the past decade several new therapies have sought to boost the patient's immune system. The approach grows out of the assumption that in cancer patients, the immune system is not able to effectively eliminate all of the cancer cells. The hope is that stimulating the immune system will increase the patient's ability to kill off cancer cells.
So far, this approach has been somewhat disappointing. In the test tube, experiments that combine immune and cancer cells are very definitely promising. The immune cells are effective in killing the cancer cells. But the situation is not repeated in vivo, where the complexity of whole-animal systems confounds the interactions between immune and cancer cells. Patrizia Griffini, in the Van Noorden laboratory, and other investigators have reported that in vivo, cancer cells do attract the attention of immune cells. Once the immune cells come face to face with the cancer cells, however, nothing seems to happen. The immune cells fail to launch the attack.
It seems that cancer cells have acquired the means to secrete large amounts of immunosuppressive messenger molecules, such as interleukin-10, transforming growth factor b and prostaglandin E2. Cancer cells also secrete molecules such as a2-macroglobulin, which scavenge immune-activating cytokines and cancer-cell-destroying proteases. In short, the cancer cells are extremely effective at manipulating their own microenvironments to their advantage.
Cancer cells may have an additional, and quite unexpected, effect on the immune cells that are supposed to kill them. Recent work by Jurg Tschopp and coworkers at the University of Lausanne in Switzerland demonstrated that the cancer cells may turn the tables on precisely those tumor-infiltrating immune cells deployed to fight the cancer. This work reveals that it is the cancer cells that in some cases are killing the immune cells.
Immune-killing cancer cells seem to have co-opted a mechanism usually employed by the killer immune cells. Almost all cells, including the cells of the immune system, carry a particular molecule on their surfaces called Fas. Fas is actually a receptor molecule that binds to another molecule called the Fas-ligand (FasL), which is normally expressed by immune cells. Under normal circumstances, immune cells hook their FasL molecule into the Fas receptor of the diseased cell. This interaction triggers a signal that causes the diseased cell to undergo apoptosis.
The Tschopp laboratory found that cancerous skin cells, specifically melanoma cells, also express FasL, whereas normal skin cells do not. Furthermore, these melanoma cells no longer express the Fas receptor. So when melanoma cells contact immune cells, they hook their FasL molecule into the immune cell's Fas receptor and cause the immune cell to undergo apoptosis. In the meantime, the melanoma cell is unaffected.
Current research is seeking to exploit such interactions to develop new anticancer therapies. For example, Claudia Friesen and her coworkers at the University of Heidelberg, Germany, found that the common anticancer drug doxorubicin enhances expression of both Fas and FasL on cancer cells. In effect, this drug causes cancer cells to kill themselves by inducing apoptosis.
Another promising class of anticancer drugs attempts to stop angiogenesis at the site of the tumor. Several recently characterized molecules, such as angiostatin and endostatin, have been shown to inhibit angiogenesis in laboratory animals. When inhibitors of angiogenesis are given to tumor-bearing animals, the tumors stop growing or, in some cases, even shrivel up. Several of these inhibitors of angiogenesis are in various phases of clinical trials and may prove to be potent against both primary cancers and secondary metastatic tumors alike. Such drugs, however, can potentially inhibit angiogenesis when it is wanted, for example, in wound healing. One solution to this problem may be to administer clotting agents selectively and directly to the tumor's blood supply, while leaving the normal blood supply unaffected.
Many recent experimental strategies against cancer attempt to compensate for or correct defective genes. The ras gene, for example, is mutated in a large number of human cancers. The Ras protein encoded by this gene is part of a pathway that responds to external growth signals by telling the cell to divide. The mutated gene encodes a protein that is permanently activated. That is, it is continually directing the cell to divide. One of the first steps in this pathway is catalyzed by an enzyme called farnesyl transferase, for which effective inhibitors have now been produced.
Other research strategies focus on restoring the function of growth-inhibiting genes. The favored strategy right now is gene therapy, which seeks to replace a mutated gene with a functioning one. Although this approach is likely to generate important therapies in the future, results so far have been disappointing. It is difficult to get the replacement gene to function properly and at levels that deliver therapeutic benefits.
In addition to efforts that seek to fight the primary tumor, much work has been focused on halting metastasis. Two main targets have provided the focus for new antimetastatic strategies. One target has been the adhesion molecules that link a cell to its original organ and that later allow it to attach to a new organ. The second focus for drug intervention has been the proteases that allow cells to chew themselves out of and into tissues.
As we have already seen, cells become unattached from their hosts by ceasing to make the adhesion molecules—such as E-cadherin—that connect them to surrounding cells. The obvious antimetastatic strategy would be to restore adhesion-molecule synthesis and prevent cancer cells from leaving their original site. One very active avenue of research involves gene-replacement therapy, in which functioning genes for the appropriate adhesion molecules could be delivered to cancer cells. This approach has worked in the test tube, but it is still far from being applicable at the bedside.
It may also be possible to modulate the relationship between integrins and the molecules to which they bind in the connective-tissue matrix. Integrins may be involved in angiogenesis as well as cell migration and the interactions between cancer and endothelial cells. For many integrins, the specific sequence of amino acids arginine-glycine-aspartate seems to be important for adhesion. Interventions have targeted this particular sequence, and have, in fact, been shown to reduce development of metastatic tumors in experimental situations. Still, these interventions are not yet ready for clinical applications.
Also interesting targets for drug intervention are the various proteases that allow metastatic cells to enter and exit tissues. Currently, only one inhibitor of MMPs, developed by British Biotech in Annapolis, Maryland, is in clinical trials. Typically, MMP inhibitors are not soluble in water, which limits their usefulness as drugs. But the new drug, called marimastat, is water-soluble. In animal models of cancer, marimastat strongly inhibits tumor development and metastasis and increases the animals' survival rate. Examination of the tissue of animals that have received this drug reveals an increase in the amount of connective tissue in and around the tumors as compared with untreated animals, suggesting that the drug is effective in halting the degradation of connective tissue by MMPs. This drug is even more potent in combination with the drug cisplatin.
The drug has been clinically tested on people in advanced stages of cancer. It was found to significantly increase survival with only the minor side effects of stiffness, local pain and discomfort. Protease inhibitors such as marimastat seem very promising for reducing the incidence of metastasis in patients once a primary tumor has been diagnosed.
Members of the Van Noorden laboratory are investigating inhibitors of other proteases involved in metastasis. We have recently been working with a specific small, water-soluble inhibitor of cathepsin-B, which seems to affect normal cells very little. We have found that the drug inhibits only the cathepsin-B on the cell membrane and not the internal lysosomal stores of the protease. This differential and complete inhibition of extracellular, but not intracellular, activity indicates therapeutic promise, because it blocks only the pathologically expressed cathepsin-B and not the physiologically required stores. We gave the drug orally to rats with colon cancer that had metastasized to the liver and found that the number of their tumors was reduced by one-third, and the size of the tumors was reduced by two-thirds. The study strongly supports the notion that cathepsin-B is involved in colon-cancer metastasis to the liver.
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