BETHESDA, MD—It's not the micrometastatic cell that will kill, even though tumors may dispatch thousands of these cells into the blood stream, and it's not a 1 mm metastatic lesion that will be fatal, either, said Isaiah J. Fidler, DVM, PhD, Chairman of the Department of Cancer Biology at the University of Texas M. D. Anderson Cancer Center, speaking here in a plenary lecture at the Skeletal Complications of Malignancy symposium.
In fact, he said at the meeting, which is cosponsored by the National Cancer Institute, the University of Virginia Health System, and the Paget Foundation, a vast number of events need to go right—from the point of view of the cancer cell—for a metastatic cell to become a threat.
For metastases to occur, the cells inserted into the circulation by the mature tumor cell face an almost implausible task, he related. It is a million-to-one shot that one of those malignant cells will seed itself by not only overcoming its 600-mile-per-hour pulsating drive through the blood vessels but also finding itself positioned to have a blood supply.
“Most of the malignant cells that enter the bloodstream circulation are going to die,” Dr. Fidler said.
Added another speaker, Kenneth Pienta, MD, Professor of Internal Medicine at the University of Michigan, the 20-micron cancer cell swirls through the circulation as it travels through the body to find a target organ or bone.
“It has to do that by avoiding the antibody system and the complement system—the enzymatic cascade made up of numerous proteins that usually exist in an inactive form,” Dr. Pienta said.
However, somehow that one cell can survive its arduous journey and become a fatal growth, Dr. Fidler continued. “What we have been able to do with metastases has not been satisfactory.”
Understanding the Metastatic Cascade
To understand how to deal with the tumor, it is first necessary to understand the metastatic cascade—how the malignant cell survives the turbulent race through the blood vessels, how it finds a safe place to seed itself, and how it gets oxygen—a “nonnegotiable” requirement for survival, he said.
“If you are interested in therapy, please invest in biology.” If scientists know how the metastatic cell manipulates its microenvironment to survive, science can then manipulate that same microenvironment to make sure that the metastatic lesion never grows larger than one mm, Dr. Fidler said.
“Let me tell you, you will never die of a one millimeter tumor. In order to grow larger than a millimeter in size, it must induce vascular supply.”
Dr. Fidler outlined the basics of the metastatic cascade that follow that one-in-a-million cell that survives the chaos of tumbling through the circulation. It survives because it develops the ability to form aggregates with either lymphocytes or platelets.
“Unfortunately, platelets that were designed to stop bleeding also help some tumor cells,” he said. “They have the adhesion molecule that will bind platelets until they create multi-cell clumps.”
Arrest Cell Clumps in Distant Capillary Beds
That clump of cells can be arrested in distant capillary beds because the cells can adhere to receptors on the surface of endothelial cells, and because very few can enter the organ parenchyma where they can proliferate.
Even there, however, the cell still has a critical task, Dr. Fidler said: “If the tumor is to grow larger than a millimeter at the new site, it must respond to the microenvironment, do angiogenesis, and the process can reproduce itself.”
He knows that cells require a vascular supply and oxygen through the pioneering studies by his laboratory. “There is only one non-negotiable thing,” he told his rapt audience. “Some of you can go without sugar; some can go without pepper; some can go without this protein or that protein. But oxygen is non-negotiable. If you don't breath for four minutes, you're brain dead. There is no substitute and for the rest of your cells, probably in an hour and you're gone. No oxygen, no life.”
“Consequently, every organ of the body, every cell, is located no more than 100 microns from the nearest blood vessel. If anything is to grow bigger than that little one millimeter hunk, it had better have blood vessels at a distance of no more than a 100 microns,” he said.
He noted that one of his fellows, a neurosurgeon from Japan, sent the lab the brain metastases of a lung cancer patient. “We stained the dividing cells and measured the distance of the dividing cells from the nearest blood vessel,” Dr. Fidler related.
“After about 500 measurements, we found that every dividing cell was less than 100 microns—an average of 73 microns from a blood vessel. And all the apoptotic cells exceeded 150 microns.”
That knowledge is critical, Dr. Fidler said because if apoptosis can be induced in the tumor's endothelial cells, oxygen will not be able to get to the tumor.
With this hypothesis in mind, Dr. Fidler and colleagues set up animal studies that used the targeted agent imatinib and the cytotoxic agent paclitaxel in human metastatic prostate cancer. Imatinib, he demonstrated, targeted growth factors that prevented the tumor from developing an oxygen supply.
“The vast majority of the dying cells happen to be blood vessel cells,” he noted. “Once you kill the blood vessel cells, everything else will fall apart. So we are directing our anger here against the endothelial cells.”
While mice that were not treated with the combination all developed tumors, only about one fourth of the animals treated with the imatinib-paclitaxel combination had tumors, Dr. Fidler reported.
Subsequently, in a clinical trial that translated the laboratory work to the clinic, 21 patients were treated with imatinib at 1,600 mg per day and docetaxel. “After several months of treatment, 67% of the patients responded nicely,” he said. “We have 50% long-term responders.”
The treatment protocols are continuing using combinations of imatinib and taxanes—a combination that requires that clinicians accept three principles, he said:
- “Targeted therapy requires a target”—meaning that if imatinib is used, tumors should express the platelet-derived growth factor receptor.
- “Heterogeneous disease cannot be treated by homogeneous therapy—Multimodality therapy is the name of the game.”
- “Chronic diseases require chronic treatment—in other words, management. I learned in my medical school classes that you don't treat acute diseases chronically. By the time you start chronic treatment your patient will die. And you don't treat chronic diseases acutely.”
For example, he noted, tuberculosis is not treated in one week—it requires nine months of incubation and nine months of treatment. “Cancer is a chronic disease. The idea that we can cure it is not necessary,” he continued. “If we maintain somebody like myself with diabetes—I have to take pills every day for the rest of my life and I hope to take them for another 20 years—why not cancer?”