HE LARGE MAJORITY OF LUNG CANCERS are caused by carcinogens and tumour promoters ingested via cigarette smoking,” says the twelfth edition of Harrison’s Principles of Internal Medicine. The statement is scienti cally incorrect, despite the truth it contains.
Smoking no more causes cancer of the lung than being thrown into deep water causes drowning. Fatal as immersion in deep water can be to the unprotected non-swimmer, for someone who swims well or is equipped with a life jacket, it poses little risk. A combination of factors is necessary to cause drowning.
It is the same with lung cancer.
Smoking vastly increases the risk of cancer, not only of the lung but also of the bladder, the throat and other organs. But logic alone tells that us it cannot, by itself, cause any of these malignancies. If A causes B, then every time A is present, B should follow. If B does not follow A consistently, then A cannot, by itself, be the cause of B—even if, in most cases, it might be a major and perhaps necessary contributing factor. If smoking caused lung cancer, every smoker would develop the disease.
Several decades ago, David Kissen, a British chest surgeon, reported that patients with lung cancer were frequently characterized by a tendency to “bottle up” emotions.1 In a number
of studies, Kissen supported his clinical impressions that people with lung cancer “have poor and restricted outlets for the expression of emotion, as compared with non-malignancy lung patients and normal controls.”2 The risk of lung cancer, Kissen found, was ve times higher in men who lacked the ability to express emotion e ectively. Especially intriguing was that those lung cancer patients who smoked but did not inhale exhibited even greater repression of emotion than those who did. Kissen’s observations implied that emotional repression works synergistically with smoking in the causation of lung cancer. The more severe the repression, the less the smoke damage required to result in cancer.
Kissen’s insights were con rmed in spectacular fashion by a prospective study German, Dutch and Serbian researchers conducted over a ten-year period in Cvrenka, in the former Yugoslavia. The purpose of the study was to investigate the relationship of psychosocial risk factors to mortality. Cvrenka, an industrial town of about fourteen thousand inhabitants, was chosen partly because it was known to have a high mortality rate and partly because its stable population base permitted easier follow-up.
Nearly 10 per cent of the town’s inhabitants were selected, about one thousand men and four hundred women. Each was interviewed in 1965–66, with a 109-item questionnaire that delineated such risk factors as adverse life events, a sense of long-lasting hopelessness and a hyper-rational, non-emotional coping style. Physical parameters like cholesterol levels, weight, blood pressure and smoking history were also recorded. People with already diagnosed disease were excluded from the research project.
By 1976, ten years later, over six hundred of the study participants had died of cancer, heart disease, stroke or other causes. The single greatest risk factor for death—and especially for cancer death—was what the researchers called rationality and anti-emotionality, or R/A. The eleven questions identifying R/A measured a single trait: the repression of anger. “Indeed cancer incidence was some 40 times higher in those who answered positively
to 10 or 11 of the questions for R/A than in the remaining subjects, who answered positively to about 3 questions on average…. We found that smokers had no incidence of lung cancer unless they also had R/A scores of 10 or 11, suggesting that any e ect of smoking on the lung is essentially limited to a ‘susceptible minority.’”3
These ndings do not absolve tobacco products or cigarette manufacturers of responsibility in the prevalence of lung cancer—
on the contrary. All the thirty-eight people in the Cvrenka study who died of lung cancer had been smokers. The results indicated that for lung cancer to occur, tobacco alone is not enough:
emotional repression must somehow potentiate the e ects of smoke damage on the body. But how?
Psychological in uences make a decisive biological contribution to the onset of malignant disease through the interconnections linking the components of the body’s stress apparatus: the nerves, the hormonal glands, the immune system and the brain centres where emotions are perceived and processed.
Biologic and psychological activity are not independent; each represents the functioning of a super-system whose components can no longer be thought of as separate or autonomous mechanisms. The past quarter century of scienti c inquiry has supplanted the traditional Western medical view of a split between body and mind with a truer, more unitary perspective. Candace Pert, a leading American researcher, has written that “the conceptual division between the sciences of immunology, endocrinology, and psychology/neuroscience is a historical artifact.”4 Psychoneuroimmunology—or, more comprehensively and accurately, psychoneuroimmunoendocrinology—is the name of the discipline that studies the interrelated functions of the organs and glands that regulate our behaviour and physiological balance.
The brain, nervous system, immune organs and immune cells and the endocrine glands are joined together through several pathways. As more research is done, more links are likely to be
discovered. The combined task of this
psychoneuroimmunoendocrine (PNI)* system is to ensure the development, survival and reproduction of each organism. The
interconnections among the components of the PNI system enable it to recognize potential threats from within or without, and to respond with behaviours and biochemical changes coordinated to maximize safety at minimal cost.
The various parts of the PNI super-system are wired together by nervous system connections, some of them only recently identi ed.
For example, the immune centres—previously thought of as acted on only by hormones—are extensively supplied with nerves. The so-called primary immune organs are the bone marrow and the thymus gland, located in the upper chest in front of the heart.
Immune cells maturing in the bone marrow or in the thymus travel to the secondary lymph organs, including the spleen and the lymph glands. Fibres issuing from the central nervous system supply both primary and secondary lymph organs, allowing instant communication from the brain to the immune system. The hormone-producing endocrine glands are also directly wired to the central nervous system. Thus the brain can “talk” directly to the thyroid and adrenal glands, or to the testes and ovaries and other organs.
In turn, the hormones from the endocrine glands and substances produced by the immune cells directly a ect brain activity.
Chemicals from all these sources attach to receptors on the surfaces of brain cells, thereby in uencing the organism’s behaviour. We have all had the experience described in medical language as
“sickness behaviour,” which illustrates the action of immune products on the brain. A group of chemicals called cytokines, secreted by immune cells, can induce the feelings that prompt us to call in sick to our workplace—fever, loss of appetite, fatigue and increased need for sleep. Distressing as they are, such rapid adaptations are designed to conserve energy, helping us to overcome illness. Inappropriate secretion of the same substances, however, would interfere with normal functioning—for example, by causing excessive fatigue or chronic fatigue.
It is astonishing to learn that lymph cells and other white blood cells are capable of manufacturing nearly all the hormones and messenger substances produced in the brain and nervous system.
Even endorphins, the body’s intrinsic morphine-like mood-altering chemicals and painkillers, can be secreted by lymphocytes. And these immune cells also have on their surfaces receptors for the hormones and other molecules originating in the brain.
In short, in addition to the unifying network of nerve bres that wire together the various components of the PNI super-system, there is also constant biochemical cross-talk among them. The myriad products they can each send to or receive from the others enable them all to speak and understand the same molecular language and to respond, each in its own way, to the same signals.
The PNI system is like a giant switchboard, always alight with coordinated messages coming in from all directions and going out to all directions at the same time. It follows, too, that whatever short-term or chronic stimulus acts on any one part of the PNI system, it has the potential to a ect the other parts as well.
What makes possible the versatile interactive functions of the PNI system? A microscopic look would reveal numerous receptor sites on the surface of each cell to which the common molecular messengers can bind. As Candace Pert reports, a typical nerve cell, or neuron, may have millions of receptors on its surface: “If you were to assign a di erent color to each of the receptors that scientists have identi ed, the average cell surface would appear as a multicolored mosaic of at least seventy di erent hues—50,000 of one type of receptor, 10,000 of another, 100,000 of a third, and so forth.”5
The messenger molecules and most of the hormones are made of amino acids, the basic building blocks of protein. They are called peptides, the technical name for longer chains of amino acids.
None of these chemicals are restricted to any one area or organ of the body. An eminent neuroscientist has suggested the term
“information substances” to describe the entire group, because they each carry information from one cell or one organ to another.
There are multiple potential interactions between information substances emanating from each part of the PNI system and cell types in each other part.
The hub of the PNI system is the hypothalamic-pituitary-adrenal nexus: the HPA axis. It is through the activation of the HPA axis that both psychological and physical stimuli set in motion the body’s responses to threat. Psychological stimuli are rst evaluated in the emotional centres known as the limbic system, which includes parts of the cerebral cortex and also deeper brain structures. If the brain interprets the incoming information as threatening, the hypothalamus will induce the pituitary to secrete an adrenocorticotropic hormone. ACTH, in turn, causes the cortex of the adrenal gland to secrete cortisol into the circulation.
Simultaneously with this hormonal cascade, the hypothalamus sends messages via the sympathetic nervous system—the ight-or- ght part of the nervous system—to another part of the adrenal, the medulla. The adrenal medulla manufactures and secretes the ight- ght hormone, adrenalin, which immediately stimulates the cardiovascular and nervous systems.
The same in uences that the organism is most likely to interpret as emotionally stressful are, not surprisingly, also the most powerful psychic triggers for the HPA axis: “Psychological factors such as uncertainty, con ict, lack of control, and lack of information are considered the most stressful stimuli and strongly activate the HPA axis. Sense of control and consummatory behaviour result in immediate suppression of HPA activity.”6
Consummatory behaviour—from the Latin consummare, “to complete”—is behaviour that removes the danger or relieves the tension caused by it. We recall that stress-inducing stimuli are not always objective external threats like predators or potential physical disasters but also include internal perceptions that something we consider essential is lacking. This is why lack of control, lack of information—and, as we will see, unsatis ed emotional needs (e.g., lack of love), trigger the HPA axis.
Consummation of such needs abolishes the stress response.
Given the biochemical and neurological cross-in uences within the PNI system, we can readily understand how emotions are able to interact with hormones, immune defences and the nervous system. In cancer causation, disturbed hormonal activity and
impaired immune defences both play a role. Lung cancer is a prime example.
The mechanistic view holds that cancer results from damage to the DNA of a cell by some noxious substance—for example, tobacco-breakdown products. This perspective is valid as far it goes but cannot explain why some smokers develop cancers while others do not, even if the amount and type of tobacco they inhale are exactly the same. The unanswered questions are, Why are the cells of some individuals more susceptible than those of others?
Why does DNA repair occur in some people but not in others? Why do the immune system and other defences keep cancer at bay in some people but not in others? What accounts for vast di erences in cure or disease progression from one person to the next, even when the identical cancer is diagnosed at exactly the same stage and even when all other factors—age, gender, income, general health—are exactly matched?
Genetic variations may explain these issues in some cancers, although, as we have seen with breast cancer, in the majority of people heredity does not play a role in cancer causation. Lung cancer, speci cally, is not a genetically transmitted disease, nor is the damage to genes in lung cancer due to heredity.
The development of any malignancy progresses through several stages, the rst of which is initiation, the process by which a normal cell becomes transformed into an abnormal one. Cancer may be seen as a disease of cell replication. The normal processes of cell division and cell death are somehow subverted. A cell that should give rise to healthy o spring escapes from control and divides into malformed facsimiles that replicate themselves without regard to the biological needs of the organism. With millions of cells dying or being formed in the body every day, natural accident would, by itself, lead to a great number of spontaneous abnormal transformations. “It’s a fact that every one of us has a number of tiny cancerous tumours growing in our bodies at every moment,”
writes Candace Pert.
Tobacco smoke has a directly damaging e ect on the genetic material of lung cells. It has been estimated that for the initiation
of cancer, lung cells have to acquire as many as ten separate lesions or points of damage on their DNA. Yet, no matter where in the body, such genomic damage “seldom leads to tumour formation. This is principally due to the fact that most primary lesions are transient and are readily eliminated by DNA repair or cell death.”7 In other words, DNA repairs itself or the cell dies without replicating its damaged genetic material—which, no doubt, accounts for the fact that most smokers do not develop clinical lung cancer. Where cancer does arise, either DNA repair or the normal process of cell death must have failed. In a 1999 review of psychological e ects on lung cancer, researchers from the Ohio State University College of Medicine wrote: “Faulty DNA repair is associated with an increased incidence of cancer. Stress may alter these DNA repair mechanisms; for example, in one study, lymphocytes from psychiatric inpatients with higher depressive symptoms demonstrated impairment in their ability to repair cellular DNA damaged by exposure to X-irradiation [X-rays].”8 Impaired DNA repair has also been documented in studies of stressed laboratory animals.
Apoptosis is the scienti c term for the physiologically regulated death necessary for the maintenance of healthy tissues. Apoptosis ensures normal tissue turnover, culling older cells with weakened genetic material, leaving room for their healthy and vigorous o spring. “Dysregulated apoptosis contributes to many pathologies, including tumour production, autoimmune and immunode ciency diseases, and neurodegenerative disorders.”9
Steroid hormones released through the activity of the HPA axis help regulate apoptosis in a number of ways. Habitual repression of emotion leaves a person in a situation of chronic stress, and chronic stress creates an unnatural biochemical milieu in the body.
Perpetually abnormal steroid hormone levels can interfere with normal programmed cell death. Also participating in cell death are natural killer cells. Depression—a mental state in which repression of anger dominates emotional functioning—interacts with cigarette smoking to lower the activity of NK cells.10
In short, for cancer causation it is not enough that DNA damage occur: also necessary are failure of DNA repair and/or an impairment of regulated cell death. Stress and the repression of emotion can negatively a ect both of those processes. The ndings of the Cvrenka investigators and of the British surgeon David Kissen make physiological sense when we consider the rst stage of malignant transformation, that of initiation.
A two-part article published in the Canadian Medical Association Journal in 1996 reviewed the role of the PNI system in health and disease. “In healthy people,” noted the authors, “neuroimmune mechanisms provide host defence against infection, injury, cancer, and control immune and in ammatory reactions, which pre-empt disease.”11 Disease, in other words, is not a simple result of some external attack but develops in a vulnerable host in whom the internal environment has become disordered.
Subsequent phases of cancerous change are promotion and progression. Having escaped the normal regulatory mechanisms that should have prevented their survival, the newly malignant cells continue to divide, leading to the formation of a tumour. At this stage, tumour growth can be inhibited or supported by the body’s internal environment. The PNI super-system comes into play. Acting chie y through hormonal regulation by the HPA axis, it creates a milieu in the body tissues that is either receptive or hostile to the growth and spread of cancer.
“The chronic psychological status of the individual may play an important role either in facilitating tumour promotion or in dampening or accentuating the impacts of environmental stress,”
Dr. Marc E. Lippman, head of the breast cancer section, Medicine Branch, National Cancer Institute, Bethesda, Maryland, has written. “The human endocrine system provides one critical mediator of interaction between psyche and tumor…. It seems inescapable that psychic factors which can evoke endocrine changes will have e ects on actual tumour biology.”12
The e ect of hormones on the growth and spread of cancer is twofold. First, many tumours are directly hormone dependent, or they arise in organs intimately involved in hormonal interactions,
such as the ovaries or the testes. Hormone-dependent cancer cells bear on their membranes receptors for various hormones capable of promoting cell growth. One example of a hormone-dependent cancer is that of the breast. It is generally understood that many breast cancers are estrogen dependent, this being the rationale for the use of the estrogen-blocking drug tamoxifen. Less well known is that some breast cancers have receptors for a broad array of other “information substances,” including androgens (male sex hormones), progestins, prolactin, insulin, vitamin D and several more—all of them secreted by the HPA axis or regulated by it.
Stress is a powerful modulator of hormonal function, as seen in both human experience and animal studies. In one experiment, researchers manipulated the dominance relationships in groups of female monkeys. Established dominance patterns were broken up.
Some previously dominant animals were forced into subordination, while subordinate ones were enabled to achieve dominant status.
Social subordination caused hormonal dysfunctions of the HPA axis and of the ovaries. “Females that were currently dominant secreted less cortisol than those who were currently subordinate.”
Dominant female monkeys had normal menstruations and higher concentrations of progesterone prior to ovulation. Subordinates ovulated less often and more frequently had impaired menstrual cycles.
When the experimental situation was altered so that previously dominant monkeys became subordinate, their reproductive function was almost immediately suppressed and their cortisol production went up. The reverse was the case in monkeys previously subordinate but newly made dominant.13
Cancers of the female gynecological organs such as the ovaries and the uterus are also hormone related. Ovarian malignancy is only the seventh most common cancer in women, but it is the fourth leading cause of cancer deaths. Of all cancers, it carries the highest tumour-to-death ratio: that is, it has the poorest prognosis.
In 1999, twenty-six hundred Canadian women were diagnosed with ovarian cancer. In the same year, fteen hundred died of it.
In the U.S. about twenty thousand women are diagnosed annually;