19.9: Cancer Cells Growth and Behavior; Cancer Treatment Strategies

Different cancer cell-types have different growth and other behavioral properties. You may have heard of slow-growing and fast-growing cancers. Colon cancers are typically slow growing. Periodic colonoscopies that detect and remove colorectal tumors in middle-aged or older people can prevent the disease (although the risks of disease and the procedure itself must be balanced). Pancreatic cancers are fast growing and usually go undetected until they reach an advanced stage.

The twin goals of medical research are to detect the different cancers early enough for successful intervention and, of course, to find effective treatments.

19.9.1 Cancer-Cell Origins, Growth, and Behavior

A single mutated cell in a tissue can become the growth point of a tumor, essentially a mass of cells cloned from the original mutated one. Benign tumors or growths (e.g., breast and uterine fibroids in women or common moles in any of us) usually stop growing and are not life threatening. They are often surgically removed for the comfort of the patient (or because cells in some otherwise-benign tumors may have a potential to become cancerous).

Malignant tumors (also called malignant neoplasms) are cancerous and can grow beyond the boundaries of the tumor itself. When tumor cells are shed, they may enter the bloodstream and travel to other parts of the body, a phenomenon called metastasis.

Cancer cells that metastasize can become the focal points of new tumor formation in many different tissues. Because cancer cells continue to cycle and to replicate their DNA, they can undergo yet more somatic mutations. These further changes can facilitate metastasis and cancer-cell growth in different locations in the body.

CHALLENGE

Where might you find mutations that could be most directly involved in metastasis?

19.9.2 Cancer Treatment Strategies

Many kinds of cancers originate in different tissues of the body (and most are capable of metastasis). All cancers share the property of uncontrolled cell division, albeit for different molecular (and not always well-understood) reasons. In addition to surgical removal of tumors, the two major cancer treatment strategies, developed in the twentieth century, all aim at disrupting replication in some way.

• Radiation therapy relies on the fact that most cells in our bodies do not divide and are thus less prone to mutational damage. They aim mutagenic radiation at tumors in the hope that the replicating DNA will be mutated at so many sites (i.e., genes) that the tumor cells can no longer survive or replicate properly.
• Chemotherapy is used to attack tumors that do not respond well to radiation or that are not easily reached by radiation technologies and to fight cancers that do not even form focused tumors (such as lymphomas and leukemias, involving lymph and blood cells). These chemotherapies also aim to derange replication or mitotic activities. For example, recall cordycepin (dideoxyadenosine triphosphate, or ddATP). When present during replication, ddATP is incorporated into a growing DNA chain, after which no additional nucleotides can be added to the DNA strand. That makes ddATP a potent chemotherapeutic disruptor of replication. Taxol is another chemo drug. In this case, it prevents the depolymerization of spindle-fiber microtubules, thus blocking mitotic anaphase and telophase in the latter part of the M and C phases of the cycle. Colchicine (a plant alkaloid) attacks cancer (and other dividing) cells by blocking microtubule polymerization in the first place, thus preventing spindle-fiber formation in mitotic prophase.

These therapies are not effective against all cancers, and of course, they don’t target specific kinds of cancer cells. Their success relies simply on the fact that cancer cells proliferate rapidly and constantly while other cell types do not. Many if not all the side effects of radiation and chemotherapies result from the damage done to normal dividing cells (e.g., hair-follicle cells, accounting for hair loss among many cancer patients; or the damage and resulting depletion of blood cells that fail to be replaced by stem cells in bone marrow). For the last twenty years or so, much research has been focused on mobilizing the body’s own immune system to create more specific, targeted cancer treatments that might avoid such side effects.

In fact, more than one hundred years ago, Dr. William B. Coley read a paper about a cancer patient who had become infected with streptococcal bacteria but had survived infection…and emerged cancer-free. He searched for and found more anecdotal reports of patients who had suffered coinfection and survived cancer-free, some of whom remained in remission for as many as seven years! In an experiment that we would have frowned upon today, Coley, then at the Memorial Sloan Kettering Cancer Center, intentionally injected a terminal cancer patient with the bacteria! Remarkably, this patient (and later, many others similarly treated) emerged tumor-free upon recovery from the coinfection. For more details, check out The Earliest Cancer Immunotherapy Trials). Coley eventually started to inject heat-killed bacteria into his cancer patients, to reduce the danger of actual infection. These injections of what came to be known as Dr. Coley’s Toxins also proved effective for some of his patients.

Dr. Coley’s son, Bradley, became a doctor and succeeded his father as head of the bone-tumor service at the Sloan Kettering. Bradley Coley successfully treated many cancer patients with his father’s toxins through the 1950s. William Coley is still thought of today as the father of cancer immunotherapy.

The effects of Coley’s “toxins” were at first thought to be a direct antitumor action. But without a known mechanism for the effect and due to remaining concerns over treating patients with infectious microbes, bacterial coinfection therapy was superseded by more predictable (somewhat) radiation and chemotherapy treatments.

Dr. Lloyd Old (also at Sloan Kettering) attempted coinfection therapy once again in the mid-1970s. In this case, he injected a vaccine made from attenuated Mycobacterium bovis (the cause of tuberculosis) directly into the bladders of patients with bladder cancer. Called the BCG (Bacillus Calmette-Guérin) vaccine, this immunotherapy was highly effective, approved by the FDA in 1990, and is still used today!

CHALLENGE

Does the BCG treatment act as a vaccine to achieve its therapeutic effects? Explain your answer.

As an understanding of immunology grew, the idea of a direct effect of the bacteria on tumors faded. Already by 1948, Coley’s phenomenon had become widely attributed to an immune response activated by the infection. In 1957 Frank Macfarlane Burnet realized that cancer cells arise from mutations in normal cells, causing their unregulated proliferation. He further suggested that cancer cells multiply by evading our immune system’s surveillance mechanism. This immunosurveillance is the job of circulating T lymphocytes (T cells) to distinguish self from non-self (i.e., “foreign” molecules and cells different from our own). For their recognition of acquired immunological tolerance (the failure of immunosurveillance) F. M. Burnet and P. B. Medawar earned the 1960 Nobel Prize in Physiology or Medicine.

Perhaps an explanation of Coley’s phenomenon and the success of BCG therapy were at hand. Were infectious agents boosting immune systems in some cancer patients to restore immunosurveillance and to allow T cells to recognize cancer cells as foreign…and kill them.

In the 1990s, scientists revisited the immune response to cancer, and by the turn of the twenty-first century, studies of cancer immunotherapy picked up steam (and more substantial research funding!). As a case-in-point, consider James Allison’s studies that identified the T-lymphocyte surface receptor that detects foreign cells and allows their destruction. He discovered that another T-cell membrane protein, CTLA-4 (cytotoxic T lymphocyte antigen 4) would bind to potential target cells and block their destruction. Allison reasoned that CTLA-4 is an immune checkpoint inhibitor that evolved to slow the destructive capacity of the cellular immune response, leading to as false immune response against that the body’s own cells. His next insight was that antibodies against CTLA-4 could relieve the checkpoint, allowing T cells to resume immunosurveillance… and if so, that it could be a strategy for attacking cancer cells! Allison eventually demonstrated that anti-CTLA-4 antibodies could kill melanoma tumors in mice and then that they were also effective against several cancers in humans. These findings would save hundreds of thousands of lives. He and Tasuku Honjo were recognized with the 2018 Nobel Prize in Physiology or Medicine for their discovery of cancer therapy by inhibition of negative immune regulation. New animal and human immunotherapy trials are promising. A few (including Allison’s) were approved in the US by the FDA (Food and Drug Administration. As somatic mutants, cancer cells make proteins that are just “foreign” enough to elicit an immune response, however slight, leading to overlapping approaches to cancer immunotherapy aimed at improving immunosurveillance to get a strong immune response to cancer-cell antigens. Some strategies, like anti-CTLA-4 immunotherapy, seek to boost that innate immune response. Others seek to isolate or to synthesize unique cancer-cell antigens in vitro, which upon injection into a patient will generate an immune response strong enough to kill the cancer cells. Different immunotherapies are summarized in the following table.

TABLE 19.1

As you can see from the table, the immuno-targeting of cancer cells has already proven to be highly effective. In some cases, the therapy is an example of personalized medicine, in which treatments are uniquely tailored to you as a patient. Yet these immunotherapies have some known issues:

• They are time and labor intensive… and costly to produce.
• While they may “cure” you, they may not work on someone else.
• Like radiation and chemotherapy, some immunotherapies come with their own unpleasant and sometimes-severe side effects.

The promise of the checkpoint blockade demonstrated by Allison continues to be an active area of research.

CHALLENGE

Remember exosomes, those bits of plasma membrane vesicle released by almost all cells with possible roles in cell-cell communication. Exosomes from natural killer (NK) immune cells were recently harvested and shown to be effective in killing cancer cells. Read the articles at NK-Cell exosomes Kill Cancer Cells or at NK-Cell exosomes Kill Cancer Cells-full paper. Then summarize in your own words and discuss what these exosomes are and how they can kill cancer cells

NOTE: The term checkpoint inhibitor in the context of immunotherapies differs from the checkpoints monitoring progress through the eukaryotic cell cycle. A more detailed discussion of cancer immunotherapies is at Cancer.gov ( Cancer Immunotherapy).