Cancer: How Lifestyles May Impact Disease Development, Progression, and Treatment

By Hymie Anisman and Alexander W. Kusnecov

Cancer: How Lifestyles May Impact Disease Development, Progression, and Treatment explores different processes that influence the efficacy of treatments and what lifestyle and behavioral modification options are available to patients to improve therapy responses, with a focus on addressing their strengths and weaknesses. The book discusses mechanisms by which particular lifestyles may affect cancer processes, including various aspects of immune functioning, inflammatory and energy-related processes, reactive oxygen species, hormonal and neurotransmitter mechanisms, the role of neurotrophins, and microbial effects. Considerable attention is devoted to the impact of psychosocial processes that indirectly affect disease occurrence, and to behavioral change methods.

• Focuses on the link between lifestyle factors (eating/diet, exercise, sleep, circadian rhythms, and stressors) in the development and progression of various types of cancer
• Addresses the contributions of lifestyle behavior to the efficacy and moderation of cancer treatments and their side effects
• Delineates mechanisms by which particular lifestyles may come to affect the cancer process

• Language: English
• Publisher: Academic Press
• Release date: Apr 9, 2022
• ISBN: 9780323985222

Hymie Anisman

Hymie Anisman received his PhD from the University of Waterloo, where he was also on faculty for two years, and has been a Professor at Carleton University, since 1994. He has also held an adjunct appointment with the Institute of Mental Health Research (Royal Ottawa Hospital) since 1993. Professor Anisman was a Senior Ontario Mental Health Research Fellow, is a Fellow of the Royal Society of Canada, and held a Canada Research Chair in Neuroscience from 2001-2015, and has since held the position of Canada Research Professor. The principle theme of his research has concerned the influence of stressors on neurochemical, neuroendocrine and immune systems, and how these influence psychological (anxiety, depression) and physical illnesses including neurodegenerative, heart disease, and cancer progression.

Book preview

Chapter 1: Cancer biology and pathology

Keywords

Immunity; Cancer; Treatment resistance; Metastasis; Hormones; Inflammation; Lifestyle; Nutrition

Outline

The distress of cancer

Extrinsic influences on cancer

The broad landscape

Features of cancer development and progression

Cancer processes

Classification

Sources of cancer

Immune surveillance

Avoiding detection: The garden of good and evil (mostly evil)

Treatment resistance

Metastases

Ingredients for cancer growth and metastasis

Nutritional and energy support

Glucose and the Warburg effect

Impact of hormones and hormone receptors on cancer processes

Inflammatory factors in the cancer process

What inflammation implies

Two faces of inflammation

Mechanisms of inflammation

Intrinsic vs extrinsic contributions to cancer occurrence

Summary and conclusions

References

The distress of cancer

Henning Mankell, the Swedish author most notable for the creation of the fictional (and somewhat morose) detective, Kurt Wallander, offered the following reflection after being diagnosed with lung and neck cancer: I remember that time as a fog, a shattering mental shudder that occasionally transmuted into an imagined fever. Brief, clear moments of despair. And all the resistance my willpower could muster. Looking back, I can now think of it all as a long drawn-out nightmare that paid no attention to whether I was asleep or awake.a

Cancer is a frightening illness. It is an intractable, often incurable disease with a history of treatments that are experienced as brutal, dehumanizing, and distressing. Even when patients are designated cancer survivors, they may be acutely aware that if the disease recurs, further treatment may be worse and less tolerable. Indeed, patients typically undergo repeated testing to determine whether the cancer has recurred, experiences that can raise questions of treatment-related damage, and the uncertainty of waiting for the other shoe to drop. To extend Mankell’s thoughts, it is not only a nightmare to process the diagnosis, but one that can extend into the postdiagnosis treatment and recovery phase.

It is not uncommon for people to believe that they have been afflicted with cancer due to factors outside their control. Perhaps unwitting exposure to environmental toxicants, inheriting mutated genes, or eating the wrong foods and not being a better or calmer person have placed them at risk—any manner of theories will pass through a person’s thoughts as they fathom the reasons for their condition. With the exception of environmental disasters—such as the Chernobyl nuclear meltdown or, more recently, the Fukushima nuclear disasters—it can be difficult to make causal links between any number of factors and the appearance of cancer. In effect, in many ways, cancer occurrence is outside an individual’s control, most especially if it is inherited. Yet in other respects, individuals do have a say in determining their destiny and can take preventative measures: not smoking, limiting sun exposure, avoiding certain foods, not becoming overweight, engaging in exercise, not becoming dependent on alcohol, being vaccinated against carcinogenic viruses—all courses of action that can reduce cancer risk.

Once an individual becomes a patient—which in and of itself is a distinction that may be significant—he or she may have some control in the selection of treatments; but often this is illusory, as they likely know and understand little about the therapies being discussed with them and often simply follow the advice of the treating oncologist. In recent years, this blind trust on the part of patients has been replaced, to a modest extent, by patients wanting to understand more about the disease and its treatment, so that they can make informed choices. It is not unusual for patients to opt for unsubstantiated alternative treatments (e.g., herbal medicines gleaned from the internet) or complementary adjunct treatments (e.g., natural treatments to supplement standard medications) either because of their mistrust or fear of traditional treatments. It is not uncommon for people to display skepticism toward medical care, and in the face of multiple alternative points of view (legitimate and illegitimate), it can leave a patient confused and open to exploitation.b

When an individual suspects the presence of cancer, this triggers a cascade of perceived and actual threats. The anticipation and anxiety related to a cancer diagnosis are invariably distressing, most notably among individuals who are less adept at dealing with uncertainty, which only leaves them more vulnerable to psychological disturbance. The distress is exacerbated with frequent delays in obtaining treatment, especially as this might allow the cancer to progress to stages of pathology that could predict undesirable treatment outcomes. These factors, together with the treatment itself, may result in patients experiencing cognitive disturbances as well as chronic anxiety, depression, and posttraumatic stress disorder (PTSD) (Cordova et al., 2017).

Overall, the diagnosis and treatment of cancer envelop the individual in a cloud of uncertainty, physical discomfort, and overwhelming psychological imbalance. The therapy itself may precipitate such problems, but it is important to note that the extreme distress of knowing, living, and even surviving cancer can contribute further to these problems. The individual’s holistic mind-body state needs to be addressed, taking into account that the person’s psychosocial relations with others also need to be considered if their battle with cancer is to have outcomes that positively impact both physical and psychological well-being.

Extrinsic influences on cancer

The etiology of disease now encompasses models that combine genetic factors with environmental chemicals, as described in Fig. 1.1. The figure illustrates the concept of an exposome, an aggregation of numerous nongenomic factors that provoke biological changes that create the circumstances for disease (Vermeulen et al., 2020). The development and progression of many types of cancer, as well as the response to cancer treatments, can be influenced by numerous environmental and lifestyle factors (diet, exercise, sleep). These may exert their effects through hormonal changes, inflammatory immune events, microbial colonization, and other biological mechanisms.

Fig. 1.1

Fig. 1.1 Both good health and illness are determined by intrinsic factors (e.g., biological processes) and extrinsic factors. These extrinsic factors, sometimes referred to as exposome, comprise psychosocial factors, lifestyles endorsed, ecosystems, and encounters with physical-chemical stimuli. Some of the many components of each sector of the exposome are provided in the figure. These are not independent of one another, and their dynamic interactions influence one another and influence biological processes that affect quality of life and health. Based on Vermeulen, R., Schymanski, E.L., Barabási, A.L., Miller, G.W., 2020. The exposome and health: where chemistry meets biology. Science 367, 392–396.

Cancer is often considered as a disease of cellular aging and prevention of this disease could be achieved, in a sense, by turning back the clock. One of the factors that may contribute to cellular aging is the accumulation of epigenetic changes in which the actions of genes are altered (suppressed or enhanced) without frank alterations of the genome. Thus, it is fascinating that a lifestyle manipulation that comprised an 8-week program in which individuals engaged in healthy eating, exercise, enhanced sleep, and relaxation training, supplemented by foods that provide probiotics and phytonutrients, was sufficient to diminish DNA-related epigenetic variations. Even this relatively short-term intervention seemed to turn back the DNA clock by about 3 years and thus could have profound implications for age-related diseases (Fitzgerald et al., 2021). Lifestyle and environmental influences are also intertwined with stress responses and behavioral and psychosocial functioning, which can affect immune and neurobiological processes. These varied factors may collectively impact cancer progression or recurrence and, importantly, may undermine the efficacy of cancer treatments.

Maintaining a healthy diet, engaging in exercise, avoiding sedentary behaviors, and diminishing stressful experiences may have benefits in preventing the occurrence of diseases, and there is reason to believe that these lifestyle choices can diminish the progression of some forms of cancer. For all its limitations standard cancer therapies have been effective in diminishing mortality stemming from many forms of cancer, but there has been considerable criticism of how slowly such advances have been made. This has encouraged the view that the answer to limit cancer deaths will largely come from modifications of lifestyles and the adoption of remedies; however, in many instances these remedies are simply too far out to be credible. Perhaps some of these approaches may have some value, but such perspective needs to be matched by convincing and reliable data that far too often haven’t been provided. So, patients are often faced with the dilemma of following the science that hasn’t uniformly provided cures on the one hand and adopting entirely untested and uncertain remedies on the other.

Within most developed countries, about 35% of people will be affected by some form of cancer, although rates in certain countries are appreciably lower (e.g., in Japan, Israel, Poland, Iceland), and nearly 30% of patients eventually develop a secondary metastatic tumor. According to the World Health Organization, cancer is the second leading cause of death globally (heart diseases are at the top) with 9.6 million deaths being attributable to some form of cancer. Of these deaths, about 70% occur in low- and middle-income countries, with various lifestyle factors (cigarette smoking, alcohol consumption, diet and obesity, poor food choices, and lack of exercise) being the greatest contributors. In ensuing chapters, we will consider these and other risk factors in greater detail, along with the possibility that avoiding or modifying these risks can be done through sensible prevention strategies.

The frequency of cancer occurrences coupled with the difficulties so often encountered during and after treatment led to altered patient care strategies. Among other things, this required continued surveillance regarding the individual’s well-being and the recurrence of illness, and because of the protracted effects of cancer and its treatment, the development of other health problems needed to be considered. This entailed the involvement of specialties other than oncology (e.g., endocrinologists, dieticians, physiotherapists, occupational therapists, social workers, and specialists to deal with pain management), and greater patient engagement in selecting their treatment. There was also an obvious need for patient mental health to be considered in much greater depth than it had been previously, which encouraged the inclusion of clinical psychologists and/or psychiatrists in attending to patient needs. The availability of such broad treatment teams was thought to improve quality of life for patients, and there was the belief—albeit still debatable—that this would enhance the effectiveness of chemotherapy and radiation therapy.

The broad landscape

As depicted in Fig. 1.2, efforts to keep cancer patients alive longer have improved markedly over the past four decades, although for some cancers the advances have been limited. These data reflect the situation in the United States but are matched by data from the United Kingdom, Canada, Australia, New Zealand, and much of the European Union (EU) (Carioli et al., 2020). In developing countries, the situation has been improving, but still lags Western countries. What this figure does not show is that no matter which country is examined, disparities exist with sex, ethnicity (race), and socioeconomic status (e.g., Ginsburg et al., 2017). Likewise, it does not portray the physical and mental cost of the illness and its treatment, nor what life is like for cancer survivors. This can vary with the treatments received, the individual’s age, and a constellation of psychosocial factors. Typically, life span might not be the only or even the most important issue that preoccupies cancer patients. Instead, they may be more concerned with health span following treatment, which essentially amounts to the years lived without further illness or disability, defining the capacity to which they are happy and fulfilled.

Fig. 1.2

Fig. 1.2 Five-year survival rates determined over a 36–37-year period increased appreciably for several types of cancer (e.g., leukemia, myeloma) or have become highly treatable (prostate, thyroid cancer) or moderately treatable illnesses (melanoma, breast, uterine, bladder, and kidney cancer). Some improvements were also realized with esophageal, lung, liver, and pancreatic cancer, but the outlook for these forms of cancer have generally been grim. Figure and caption from Roser, M., Ritchie, H., 2018. Our World in Data: Cancer. https://ourworldindata.org/cancer. Retrieved Jan 2020.

The most recent update regarding the overall occurrence of cancer indicated that incidence rates for cancer among males have been stable, whereas that among women increased somewhat between 2013 and 2017, and this was also apparent among children, adolescents, and young adults (Islami et al., 2021). As depicted in Fig. 1.3, these statistics vary appreciably across different forms of cancer. In contrast, in both sexes, cancer-related deaths declined during this period, although again this depended on the nature of the cancer and varied between sexes. Among males, cancer-related death rates declined in 11 of the 19 forms of cancer, and in females, a decline was reported in 14 of the 20 types of cancer, including some of the deadliest cancers (e.g., melanoma, lung cancer).

Fig. 1.3

Fig. 1.3 Average annual percent change (AAPC) in age-standardized, delay-adjusted incidence rates for the period 2013–17 for all sites and the 18 most common cancers in men and women of all ages, all races/ethnicities combined. The AAPC was a weighted average of the annual percent change (APCs) over the fixed 5-year interval (incidence, 2013–17) using the underlying joinpoint regression model, which allowed up to three different APCs, for the 17-year period 2001–17. AAPCs were significantly different from zero (two-sided P  < .05), using a t -test when the AAPC laid entirely within the last joinpoint segment and a z -test when the last joinpoint fell within the last 5 years of data, and are depicted as solid-colored bars ; AAPCs with hash marks were not statistically significantly different from zero (stable). Abbreviations: NOS , not otherwise specified. From Islami, F., Ward, E.M., Sung, H., Cronin, K.A., Tangka, F.K.L., et al., 2021. Annual report to the nation on the status of cancer, part 1: national cancer statistics. J. Natl. Cancer Inst. djab131.

As encouraging as it is to see increased survival among cancer patients, one should not assume that cancer elimination equates with full health restoration. In destroying cancer cells, standard cytotoxic treatments also kill healthy cells and may engender inflammation in many neighboring cells. Aside from the possibility of the cancer recurring, treatments may cause organ damage (including the heart, lung and airways, liver, and kidney), osteoporosis, persistent pain, sexual dysfunction and infertility, lymphedema (lymphatic fluid buildup in tissues, which produces painful inflammation, swelling, and restricted movement), and in response to some treatments, urinary or bowel (fecal) incontinence. Some of these consequences may not appear until years later. For instance, among individuals who survived childhood cancer (e.g., leukemia), it was common (80%) for a severe illness to occur before survivors reached 45 years of age. The protracted effects of therapies range broadly. Some were not life-threatening and were often being as manageable, such as hearing loss (62%), memory problems (25%), male infertility (66%), and female infertility (12%). Others, however, comprised serious life-threatening conditions, including cardiac disturbances (in 63% of individuals), abnormal lung functioning (65%), and endocrine dysfunction (61%). In some instances, a second cancer appeared, possibly owing to genetic factors that favor the emergence of different types of cancer or perhaps due to the initial cancer treatment. Gentler treatments are thought to diminish these long-term side effects, and a personalized treatment approach may offer the hope of diminished proactive effects.

The cancer treatment landscape has been changing over the past decade, but it is certain that much more needs to be achieved. Historically, the focus of most research had been on factors related to cancer diagnosis and treatment with less attention devoted to cancer prevention. But it is now common knowledge that behavior is a common mode of facilitating the onset of some cancers—e.g., to avoid lung, throat, and skin cancer the prescription is don’t smoke and avoid prolonged direct exposures to the sun. It would be rare to find people who would consider such advice as inappropriate, although it wasn’t always accepted that smoking caused cancer or that certain rays of the sun can promote melanoma. Indeed, until a few decades ago children and teenagers spent as much time as possible in the sun, smothered in lotions that would enhance their tans, rather than blocking the harmful ultraviolet rays. Equally, the influence of diet, exercise, stress, and sleep on cancer occurrence had frequently been ignored or simply neglected, despite these lifestyle factors receiving attention in the context of heart disease and type 2 diabetes. It ought to go without saying that preventive strategies are largely an individual’s responsibility, but community-level preventive approaches might facilitate the adoption of methods to limit cancer development. Remarkably, however, until about a decade ago most people were unaware of the linkages between many lifestyle factors (e.g., diet, exercise) and cancer.c At that time it was not uncommon for people to believe that cancer was caused by injury, or that irreligiosity in some manner contributed to cancer occurrence. As well, there was limited awareness that diet or exercise was linked to cancer, and it was not unusual for people to believe that alternative medicines were as effective as standard therapies in cancer treatment (Lord et al., 2012). Since then, there has been greater awareness of the sources of cancer occurrence, but a significant number of people are still unaware of the cancer risks associated with obesity or alcohol consumption (e.g., Meyer et al., 2019).

Meta-analyses and systematic reviews

The rate of scientific output has increased exponentially over the years, and as much as this ought to be advantageous, it is not unusual for inconsistent findings to be reported. This could occur owing to subtle or pronounced procedural differences between studies, or the findings of some studies may simply be unreliable for any number of reasons. Thus, it has become increasingly desirable to have cogent reviews of the literature that both synthesize the available literature and facilitate conclusions regarding where the bulk of evidence lies. Meta-analyses became a progressively more popular way of organizing and then reviewing large swaths of research while taking into account the effect size in each study (i.e., the strength of associations that exist between variables) and the number of participants in these studies (studies with a small number of participants are usually seen as being more prone to unreliable outcomes). Ordinarily, before undertaking the analyses, investigators specify inclusion and exclusion criteria for studies. This may entail the type of participants or research approach adopted in the studies, such as whether they involved retrospective or prospective approaches or whether they consisted of random controlled trials. By rigorously following sets of criteria, estimates can be determined as to how reliable and meaningful the results are, and what key variables could moderate the observed relationships.

Another approach of summarizing large amounts of data has entailed systematic reviews. These analyses follow rigorous guidelines concerning the specific issues to be addressed, the identification of the relevant work that should be included or excluded, and how to assess the quality of the research considered. Often, the data come from quantitative analyses, but qualitative analyses (e.g., individual narratives) can be included, and meta-analyses can be incorporated as part of a systematic review. It is of great importance that not all studies are given equivalent weight in that methodological issues might be considered by independent raters who determine the goodness of studies and hence the weight attributed to them. Numerous clinical conditions have been assessed using these approaches, including therapeutic methods to treat illnesses, the side effects of various treatments, and the effectiveness of social and public health interventions, as well as cost-benefit analyses related to the risks associated with particular treatments relative to what could be expected if treatments had not been applied.

Meta-analyses and systematic reviews have been remarkably effective in summarizing large sets of studies to bring order and understanding disparate findings. However, these analyses can also be misleading. These reviews are only as good as the inclusion and exclusion criteria that are used in the analyses. For instance, a given analysis might include both observational studies and randomized controlled studies whereas another analysis might only include the latter, thus they may provide different conclusions. Likewise, some analyses might ignore certain variables, such as sex differences, and hence biased or inexact conclusions may be derived. Another serious shortcoming of these analyses is that they can only include the available reports, which are typically those that have been published in peer-reviewed journals. Most often, however, published reports comprise those that showed significant outcomes, whereas studies in which significant effects are not obtained are often never published. As a result, one could easily be misled to believe that a given treatment is effective when, in fact, many more experiments indicated otherwise. It may unfortunately take many years of research before it becomes apparent that certain treatments weren’t as effective as initially claimed.

Features of cancer development and progression

Cancers are characterized by uncontrolled cell growth, culminating in tumor development that can destroy surrounding tissue and spread promiscuously to other regions. Cancer cells are typically considered to be cells that can escape the main tumor mass (i.e., the primary tumor), migrate to remote sites via the vascular or lymphatic systems, and establish a new cancer colony (a metastasis or secondary tumor). For example, a biopsy on a lung tumor might reveal that the cells are actually from another organ (say, the pancreas), thereby establishing the tumor as a secondary tumor, and evidence of metastatic spread from the primary source (the pancreas). Such metastasizing cells present with a unique gene signature, which distinguishes them from more stable, nonmigrating cells that remain in the primary tumor. To a large degree cancer cells display unprogrammed and/or mutated behavior characterized by runaway mitosis, which becomes biologically threatening when unrestrained. The persistent cell division is a result of numerous cellular pathways being coopted to enable cells to avoid or disregard the inherent constraints on cell growth that are observed in healthy cells. In so doing, they modify their microenvironment to favor their survival and proliferation, drawing on energetic processes needed by normal cells and avoiding surveillance by cytotoxic immune cells. In short, cancer cells are capable of breaking through barriers that might otherwise restrict their growth and can spread to other organs. Such a situation is malignant because it impairs the function of colonized tissues and organs. In contrast, benign tumors do not invade or infiltrate into the cellular network of surrounding tissues or organs. These tumors grow as an isolated mass with their own capsule and, with some exceptions, lack metastatic capacity. Benign tumors do grow, but slowly, and in the best-case scenario, simply stop growing. And while they do not interfere with the physiological and biochemical functions of intrinsic cells in a tissue, they do compress nearby structures, thereby causing pain or other medical complications that will warrant their removal. Otherwise, benign tumors are sometimes judged to be better left alone.

In their analysis of the elements that make for cancer development and spread, Hanahan and Weinberg (2011) identified six characteristics that are common among many forms of cancer. These hallmarks of cancer are shown in Fig. 1.4. Cancer cells are seen as self-sufficient in being able to respond to cell growth signals and insensitive to signals that inhibit growth. Moreover, in addition to being able to evade apoptosis (programmed cell death to eliminate cells that are damaged or contain potentially dangerous mutations), they have a remarkable capacity to replicate and to promote and sustain their growth. They can stimulate blood flow to themselves (angiogenesis), evade attempts of the immune system to destroy them, and can invade local tissues and metastasize. Beyond these features, inflammatory processes, and the ensuing genetic dysregulation, might represent a seventh essential characteristic that supports cancer processes.

Fig. 1.4

Fig. 1.4 The six hallmarks of cancer that facilitate their growth and survival. From Hanahan, D., Weinberg, R.A., 2011. Hallmarks of cancer: the next generation. Cell 144, 646–674.

In addition to these fundamental processes, several biomechanical features of tumors may sustain and enhance their growth and spread. Specifically, owing to permeable blood vessels in tumors that leak blood plasma into tissues surrounding the tumor, together with limited drainage of lymphatic fluid, elevated interstitial fluid pressure may be created that causes edema, the release of growth factors, and the facilitation of cancer cell invasion of nearby and distal tissues. As well, the proliferating and migrating cancer cells compress blood and lymphatic vessels, thereby disturbing blood flow and hence diminish immune cell presence and limit oxygen to the region and may concurrently hinder drug presence that would otherwise limit tumor growth. At the same time, the immune microenvironment surrounding a tumor may limit the access of immune cells, and interactions between cancer cells and their microenvironment may be disturbed, consequently affecting signaling pathways that may affect cancer cell invasion and metastasis.

The tumor microenvironment is complex, typically being distinct from that of normal cells with respect to oxygen availability, metabolic processes, acidity, and interstitial fluid pressure. This environment, the battlefield between the cancer cells and a person’s defenses, holds considerable sway over tumor progression and the efficacy of various treatments. Cancer cells can influence and be influenced by the lymphocytes that had infiltrated the area as well as by the presence of stromal cells that make up connective tissues, fibroblasts (a type of cell present in connective tissue), blood vessels, and the extracellular matrix. The latter, a noncellular component present in tissues and organs, comprises the scaffolding for cells. Accordingly, approaches could be adopted to take advantage of the microenvironment to enhance the efficacy of varied therapeutic strategies.

Cancer processes

More than 200 forms of cancer have been identified, involving different organs and different cell types. In general, these cancers fall into distinct classes (see Table 1.1) and are also described by their stage of progression (the size of the tumor and how extensively it has spread). Cancers can also be distinguished from each other based on their genetic and epigenetic signatures, as well as the speed of expansion (viz., slow vs fast growth). They are also differentiated according to sensitivity to immune and hormonal mechanisms, such as whether they are influenced by certain hormones or inflammatory processes. Each type of cancer may contain multiple subtypes. Breast cancer, for instance, may comprise ductal, lobular, tubular, invasive, infiltrating, mucinous, and medullary types, and can also be classified based on whether certain receptors are present, such as those for estrogen, progesterone, and HER2 (as in the case of triple-negative breast cancer). By virtue of this heterogeneity of cell types, each form of cancer requires a specific therapy, and even within a given cancer type, differences might prompt specialized treatments.

Table 1.1

Modified from Anisman, H., 2021. Health Psychology: A Biopsychosocial Approach. SAGE, London.

Classification

Cancer subtypes are classified based on the tissue affected, features of the cancer, and the extent to which the cancer has progressed (i.e., stage of the disease). These serve as prognostic indicators for the probability of successful treatment or life expectancy and guide the choice of treatment. For instance, when the cancer is localized, surgery may be selected, but chemotherapy may be adopted as an adjuvant therapy to eliminate cancer cells that might persist following surgery.

The general diagnosis of cancer involves the use of a staging system that ranges from abnormal but not immediately dangerous cellular states to those that have advanced to a life-threatening pathological condition. These are summarized as follows:

•Stage 0, also referred to as carcinoma in situ, refers to cancer cells having been detected that have the potential to spread.

•Stage I, or early-stage cancer, refers to the cancer being small and localized to a specific area.

•Stage II refers to a larger cancer that has infiltrated nearby tissues or lymph nodes.

•Stage III also describes the situation in which the cancer is larger and affects nearby tissues, as well as lymph nodes that are nearby as well as those that are more distant.

•Stage IV refers to cancer that has spread (metastasized) to other parts of the body.

Several biological processes and their interactions have been implicated in the provocation and progression of cancers, including diverse hormones, growth factors, a broad assortment of immune factors, and related genetic influences, as well as immune signaling molecules, most notably cytokinesd (Thorsson et al., 2018). Given the links between cancer and immune functioning, appreciable efforts have focused on altering the immune system’s capacity to eliminate unwanted cells. However, even with the best immunotherapeutic approaches, only some types of cancer can successfully be treated, and even then, only a proportion of individuals benefit from the treatment. Nonetheless, advances on this front have been impressive, and a continuous flow of immunotherapeutic agents and combinations of agents have been derived that can treat an ever-broader range of cancers, with moderate improvements realized in the number of patients effectively treated.

BFF

Many cancers, such as lymphoma, appear across species, including in our beloved pets, which are heavily interbred, while certain species rarely develop cancers, a list that includes whales, elephants, and mole rats. What protects certain species from developing cancer, and is this common across species? Provided that they are not hunted to extinction, cross-species comparisons of long-lived animals may offer important clues regarding the factors that promote cancer occurrence or conversely render them cancer-free. In the case of elephants, it seems likely that the absence of cancer may be related to their excellent ability to eliminate damaged cells, rather than simply repairing damaged DNA, or because they have an overabundance of genes that act as tumor suppressors (Vazquez and Lynch, 2021).

Cancer is the leading cause of death in certain dog breeds, such as the Golden and Labrador retrievers who are particularly prone to lymphoma, while the beautiful Bernese Mountain dogs are susceptible to histiocytic sarcoma characterized by an abnormal elevation of macrophages, dendritic cells, and monocytes. One type of cancer, canine transmissible venereal tumor, likely stemming from a Siberian dog strain that existed about 6000 years ago, is transmitted through sexual contact. By analyzing the genetics of these tumors, useful clues may arise as to why certain cancer-driving genes have been successful (Baez-Ortega et al., 2019). Humans and their canine friends may develop several similar cancers, such as sarcomas, lymphoma and leukemia, bladder cancer, glioma, and melanoma, whereas several others are not seen in animals, including lung, prostate, and testicular cancers. Why humans are unique in developing certain forms of cancer is uncertain, although they could be related to environmental triggers or may be secondary to unfortunate adaptations to environmental and social challenges.

Despite the differences between humans and their dogs, they share environments and consume some of the same foods, and therefore where dogs may develop the same cancers the reasons may be similar to those of humans. As it happens, the efficacy of some canine cancer vaccines that are in development may be effective in preventing a variety of different cancers, and programmed stem cell transfer methods could be used to diminish canine cancers. These methodologies may facilitate the search for treatments in humans. Analysis of particular tumor types and how they are passed across generations in dogs may also have implications for the evolution of human cancers (Maley and Shibata, 2019). Finally, it’s no secret that having a dog is often good for heart health, possibly because it gets the dog’s person out walking. If, as we’ll see later, exercise can also have beneficial effects on cancer progression and treatment, it will be one more way in which dogs may be a human’s best friend.

Many cat lovers know that these wonderful creatures may also develop a variety of different cancers, some of which also occur in humans. During their lifetime, one of four cats is diagnosed with cancer, most commonly lymphoma, squamous cell carcinoma, mammary tumors, and bone cancer. At one time, when our pets developed cancer, it was unlikely that considerable efforts would be expended to extend their lives, but this has been changing in recent years, and methods have been developed to deal with cancers in pets. Because of the similarities between cancer in cats and those observed in humans, treatments in cats might provide clues as to what might be beneficial in humans. Cats often develop oral squamous cell carcinoma that is reminiscent of head and neck cancer in humans, and cats also develop triple-negative breast cancer more often than humans, providing the opportunity to study this type of cancer when these pets are treated. Pet lovers would be aghast at the thought of having cats and dogs serve as experimental subjects to evaluate treatments of cancer much like mice are used in this regard. This would be impractical for a variety of reasons, but when veterinarians go about treating their patients, important information can be obtained for the benefit of other animals and humans provided that the findings are included in broad registries.

Sources of cancer

Cancer can be developed due to hereditary and/or genetic factors (that we will discuss in Chapter 4), random DNA mutations, or those brought about by carcinogens and other extrinsic factors. To a considerable extent, the immune system is reasonably proficient in protecting against foreign invaders, but the fact that we so often become ill attests to its limitations. Of course, the remarkable capacity of the immune system may be undermined by aging, as well as the adoption of poor lifestyles, culminating in increased disease risk. It also appears that with aging, chronic infection and inflammation associated with several diseases may undermine immune functioning, thereby increasing the risk of cancers as well as cardiovascular disease and stroke.

Immune surveillance

Once immune cells detect the presence of cancer cells and decide that they need to be eliminated, a battle ensues that can result in immune cells coming out on top, but all too often cancer cells are victorious. As stated in other contexts, the immune system can win many battles, but it only needs to lose once for catastrophe to ensue. In some instances, the two sides battle to a stalemate, in which case the tumor would not appear at that time (tumor dormancy), but a breakout may occur by cancer cells as long as decades later. This begs the question as to whether lifestyle factors or stressor experiences influence the emergence of cancer during the tumor dormancy period, but convincing data one way or another remains to be provided. It should be said that although a lengthy period may exist between the first cancer cells appearing and a frank cancer being apparent, there are instances in which this period can be greatly abbreviated. In some instances, such as childhood brain cancers, the culprit cells might originally appear during the embryonic stage of development when the immune system is in a rudimentary or immature state and then manifest after birth as a cancer during early life (Vladoiu et al., 2019).

According to an early view, the immune surveillance hypothesis (Burnet, 1970), immune cells located within secondary immune organs and circulating through the body were continuously on alert for the presence of newly transformed cells. Cancer would therefore be the result of mutated cells being, for whatever reason, undetected or not destroyed by the immune system. As tantalizing as this view was, experimental evidence was scant; but a revised version of this hypothesis, a cancer immunoediting perspective, was proposed and is illustrated in Fig. 1.5 (Dunn et al., 2004; Lussier and Schreiber, 2016). Like the earlier view, the cancer process was seen as involving several phases. During the first of these, the elimination phase, innate immune cells ought to recognize the presence of cancer, giving rise to several aspects of the immune system being activated. Most prominently, cytotoxic T cells and natural killer (NK) cells can directly confront tumor cells and destroy them, whereas others are responsible for carting away dead tumor cells and depositing them in draining lymph nodes. Supplementing these immune processes were tumor-disrupting chemical mediators and endogenous genetic processes that act to suppress tumor proliferation. Thereafter, during the ensuing equilibrium phase, various immune cells continue to be called upon to engage the cancerous cells, working to eliminate them, or at best keep them at bay. Finally, during the escape phase, tumor cells can infiltrate the epithelium—the cellular layer lining the outer surface of blood vessels, organs, and varied body cavities—ultimately overrunning the body’s defenses and expanding into an uncontrolled mass.

Fig. 1.5

Fig. 1.5 The three phases of the cancer immunoediting process. Normal cells (gray) subject to common oncogenic stimuli ultimately undergo transformation and become tumor cells (red) (top). Even at early stages of tumorigenesis, these cells may express distinct tumor-specific markers and generate proinflammatory danger signals that initiate the cancer immunoediting process (bottom). In the first phase of elimination, cells and molecules of innate and adaptive immunity, which comprise the cancer immunosurveillance network, may eradicate the developing tumor and protect the host from tumor formation. However, if this process is not successful, the tumor cells may enter the equilibrium phase where they may be either maintained chronically or immunologically sculpted by immune editors to produce new populations of tumor variants. These variants may eventually evade the immune system by a variety of mechanisms and become clinically detectable in the escape phase. Figure and caption from Dunn, G.P., Old, L.J., Schreiber, R.D., 2004. The immunobiology of cancer immunosurveillance and immunoediting. Immunity 21, 137–148.

The effectiveness of the immune system is often compromised in certain diseases (e.g., AIDS) or not quite up to the job, as in aging. This can permit tumor growth to occur more readily. Several other variables, such as the presence of inflammatory factors, can also moderate tumor development during these phases. As we will see, modest inflammation has multiple beneficial actions when present for brief periods, but left unchecked, inflammation becomes chronic and can precipitate numerous problems. Moreover, cancer cells can escape immune surveillance through changes in gene functioning associated with environmental or experiential variables. This can silence genes associated with immune functioning or inhibit protective tumor suppressor genes. It had long been considered that certain genes acted as tumor suppressors, but it now seems that some genes (e.g., a gene named GNA13) not only act in this capacity but can also help tumor cells evade detection (Martin et al., 2021). Chapter 4 will describe how genetic factors and interactions between genes, as well as genes and other processes, may promote cancer occurrence and exacerbate its progression.

Avoiding detection: The garden of good and evil (mostly evil)

To devise effective treatment methods, it is necessary to understand how cancer develops, and why our immune system seems to fail us. Cancer may occur owing to random or inherited genetic mutations, those that are provoked by environmental factors or specific toxicants, and because the immune system failed to function effectively. However, rather than simply attributing cancer development to immunological missteps, it may be more profitable to also consider the talents of cancer cells in circumventing our defenses. In learning the repertoire of tricks that cancer cells use, one cannot help but marvel at how cunning they are in keeping scientists from uncovering the many ways they thwart our best efforts to eliminate them. Hopefully, by countering the ways tumor cells evade detection and survive attacks, coupled with ways of enhancing the capabilities of the immune system, progressively better methods of cancer treatment will be developed.

Circumventing defenses

Researchers attempting to devise methods to combat cancer have repeatedly encountered the devious ways by which cancer cells are able counter strategies to eliminate them. When one pathway for cancer growth was blocked, they were able to find other routes to carry out their mission, often leading to even more aggressive actions. For instance, a major stress pathway, mammalian target of rapamycin (mTOR), contributed to drug-provoked mutagenesis, but blocking this pathway did not provide beneficial actions, indicating that other pathways concurrently contributed to mutagenic outcomes. Some of these routes may be modulated by cancer-related genes, such as BRAF, MEK, and PAK, and targeting more than one of these at a time might optimize treatment responses, even if the benefits obtained were relatively transient. Similarly, targeting both BRAF and the gene that encodes insulin-like growth factor-binding protein 2 (IGFBP2), which predicts a poor prognosis among melanoma patients, provided a better treatment response than dealing with either gene separately (Strub et al., 2018). Another view has it that proinflammatory cytokines released from immune cells stimulate a protein, ITCH, which acts to modify BRAF so that it does not interact with inhibitory proteins, thereby allowing melanoma growth and metastasis (Yin et al., 2019). Immune cells are exceptionally adept at recognizing foreign invaders or the presence of cells that ought to be eliminated. Since cancer cells are a mutated form of the host’s cells, they might still bear sufficient similarity to healthy cells. This enables them to evade attack, such as displaying a type of exemption or tolerance signal to other immune cells, such as macrophages (which detect, engulf, and destroy cellular pathogens). In acute myeloid leukemia (AML), for instance, many cancer cells overexpress the gene encoding CD47, a surface molecule known to serve as a don’t eat me signal in healthy cells. This allows them to slip under the radar and evade ingestion by macrophages (Majeti et al., 2009).e Cancer cells can also be viewed as cold or immune-privileged, such that neoepitopes (new markers on a foreign particle or cell) that ought to signal attack are absent or downregulated, as in the case of pancreatic cancer, in which the high mutation rate is accompanied by very few neoepitopes. Cold tumors also comprise those that are surrounded by cells that can suppress T cells so that the tumor cells are not attacked. Furthermore, when cancer cells are attacked (e.g., by chemotherapeutic agents) they can, as a group, go into a hibernation mode until the threat has gone.

As we will see in Chapter 15, coordination occurs so immune cells do not ordinarily attack healthy cells. Specifically, checkpoint proteins (e.g., PD-1) located on immune cells serve as an off-switch when they bind to a programmed death-ligand 1 (PD-L1) protein that is present on healthy cells. This type of suppression limits immune cell attacks on self-tissue, thereby reducing autoimmune disorders, tissue allografts (transplanted tissue from another person), and rejection of the fetus during pregnancy. As sophisticated and effective as this regulatory mechanism might be, it isn’t always fully effective. Immune cells do, in some instances, turn on the self to produce autoimmune disorders, and certain cancer cells also display PD-L1, thereby taking advantage of the T cell, which fails to attack the cancer cell that is free to proliferate.

Aside from the few we have mentioned, cancer cells have many other ways of getting around immune defenses, making it much more difficult to thwart their pathological consequences. Some tumors downregulate aspects of the immune system, essentially making them invisible to T lymphocytes, while other tumors use structural defensive strategies—producing collagen and fibrin that serve as physical barriers. Tumor or infected cells ought to display features—like the presence of MICA and MICB proteins—that signal them for destruction by NK cells. However, some tumor cells acquire the ability to delete these markers, making an attack on them less likely (Ferrari de Andrade et al., 2018). Moreover, some genes, like the PARP1 gene, which encodes an enzyme involved in DNA repair, can make cancer cells less susceptible to NK cytotoxicity. By manipulating this gene, cancer stem cells were made more vulnerable to NK cells (Cerwenka and Lanier, 2018), in keeping with the notion that gene modification therapies can augment immunological tumor surveillance.

Duplicitous cancer cells engage in still other methods to avoid detection. A molecular coating on tumor cells can make them difficult to recognize by immune cells, or they may link with normal cells, thereby getting immune defenses (a friend of my friend, is also my friend). Alternatively, they might release protective factors to avoid proteins, such as metastasis suppressors, which normally would act against them. And transforming growth factor-β (TGF-β), which is produced by multiple healthy cells in the body, can be produced by lung cancer cells thereby limiting detection by NK cells (Donatelli et al., 2014). Cancer cells can also use substances within the body, such as neurotransmitters, to cloak their mutated nature when they reach particular milieus, such as the brain (essentially, hiding in plain sight).

In other cancer conditions, such as brain glioblastoma, there is a redistribution of immune cells such that circulating leukocytes are reduced, whereas an abundance of cells appears in the bone marrow, possibly through messages sent by the tumor (Chongsathidkiet et al., 2018). Glioblastomas and other types of cancer cells are highly plastic (changeable), altering their basic surface characteristics in response to a microenvironment consisting of tumor blood vessels and local immune cells and their signaling molecules, which makes the tumor more difficult to target (Dirkse et al., 2019). Indeed, gliomas are capable of adapting to the brain environment. This involves the formation of new functional synapses with nearby neurons, and glial cell release of the excitatory neurotransmitter, glutamate, which may drive the proliferation, survival, and overall invasiveness of glioma cells. In mouse models, modifying glutamate receptors on glioma cells can influence their proliferation and survival times (Venkataramani et al., 2019).

Cancer cells have still other dirty tricks to evade immune cells, deceiving them to think that they are friends rather than foes. Through their receptors, T cells produce a minute mechanical tug (a handshake in a sense) on other cells to determine whether it is a threat. Those that are not threatening maintain a weak handshake, but if they are threats, then stronger and longer handshakes occur, which leads to a cascade of immune factors to attack the foreign substance. However, unlike other foreign substances, some cancer cells have an extra molecule that can alter their handshake, causing T cells to become lethargic and less apt to function properly (Liu et al., 2016).

Cancer’s active defenses

Aside from adopting passive methods to get by the immune system, cancer cells may take an active role to facilitate their own growth. Tumor cells can disturb immune functioning by producing toxic metabolites or by influencing inhibitory pathways. This can be through the secretion of particular growth factors by tumor cells (e.g., TGF-β), which inhibits metabolism in CD4+ T cells and production of the cytokine interferon (IFN)-γ, resulting in diminished attacks on cancer cells and hence reduced patient survival. In addition, components of the innate immune system, specifically myeloid cells (i.e., granulocytes, monocytes, and tissue resident macrophages) that ought to be attacking cancerous cells can be coopted so that they become allied with cancer cells. Indeed, neutrophils that initially serve in a protective capacity may switch sides to become pro-tumorigenic (Magod et al., 2021).

Normally, the presence of integrin CD11b recruits myeloid cells to sites of damaged tissue so that a proinflammatory type of macrophage (categorized as M1) could attack tumor cells. However, tumor cells can develop the capacity to suppress CD11b functioning such that less aggressive, antiinflammatory macrophage types (called M2 macrophages) are recruited. These macrophages can act against T cells, thereby limiting their negative control over cancer cells and metastasis (Martinez and Gordon, 2014). In effect, innate immune cells may become polarized in the context of a tumorigenic environment, ultimately disrupting the cytotoxic actions of antigen-specific T cells, even producing an immunosuppressive milieu and undermining the plasticity of varied immune cells that are required to diminish cancer progression (Chang and Beatty, 2020). It should be said, however, that the plasticity which is a core characteristic of macrophages might turn out to be a good target in the treatment of varied inflammatory disorders, including cancer. Essentially, in the presence of IFN-γ, the M2 macrophage can be flipped to the M1 form, in the hope that this promotes antitumor cytotoxicity.

Macrophages and macrophage-stimulating genes are an inherent feature of the tumor environment, and while they could act against certain brain cancers, such as glioblastoma, they are able to reprogram these immune cells, thereby promoting tumor growth. Other types of macrophages have similarly been linked to enhanced tumor growth and poor outcomes, and the greater the macrophage density in breast and other cancers, the worse is the prognosis (Mantovani et al., 2017). These tumor-associated macrophages (TAMs) suppress the actions of other immune cells by releasing the inhibitory cytokine IL-10 (Ruffell et al., 2014), promoting angiogenesis (formation of new blood vessels in tumors), and facilitating metastasis. Further, in the face of some types of chemotherapy or radiation, TAMs release molecules (e.g., cathepsin) that support cancer progression. Fortunately, by inhibiting these processes, the effectiveness of treatments to detect and limit the presence of TAMs could be augmented to improve cancer therapy (Arlauckas et al., 2017) as shown for colon tumors in mice. Likewise, synergistic therapeutic actions have been achieved. For example, when an anti-CD47 (blocking the don’t eat me signal) treatment was combined with antibodies against the lung cell marker, epidermal growth factor receptor (EGFR), the efficacy of the cancer treatment was enhanced (Weiskopf et al., 2013). There are also instances in which TAMs can augment the actions of some chemotherapies, making them an obvious target to improve treatment methods (Mantovani et al., 2017).

Cancer cells display a social element, influencing their neighbors by releasing exosomes (cell-derived vesicles) that contain proteins, fats, or genetic material into the extracellular space. It had long been thought that exosomes were involved in cellular debris being tossed out, but it is now understood that they have more complicated functions, even serving cell-to-cell signaling. Exosomes may create an inflammatory milieu that leads to more aggressive cancer cells (Nabet et al., 2017), or they can infiltrate adjacent healthy cells, causing them to become cancerous. Moreover, they can transplant tumor information (e.g., tainted RNA) and prepare cancer cells for metastatic travel to distant sites. As exosomes are associated with immune functioning and can influence the development of numerous diseases, including cancer, the notion arose that they could potentially be engineered to carry toxic payloads, such as immune modulators, chemotherapeutic, or immunotherapeutic agents, to destroy tumor cells (Kalluri and LeBleu, 2020). To be sure, this point hasn’t been reached yet, but since exosomes (and their contents) can be detected in biological fluids, they may be useful as biomarkers that could operate as multicomponent readouts related to cancer diagnosis.

At this point, it’s clear that cancer is a complex and slippery problem. Our reasons for providing this compendium of the different ways by which cancer cells can circumvent our defenses are twofold. One was simply to illustrate the powerful capacity of cancer cells to survive, which points to the challenges faced in developing ways to get rid of them. The second reason was to highlight the progress made to counter the nefarious efforts of cancer cells. Cancer still takes many lives and generates considerable fear. But through one step at a time, even if seemingly baby steps, important advances have been made. To this point, we have primarily considered pharmacological treatment strategies that attempted to thwart the capabilities of cancer cells or that enhanced immune functioning. Little, in contrast, was said about how lifestyle factors could be used as an auxiliary method to facilitate or enhance the effects of other treatments, which could go a very long way in prophylactically stemming cancer occurrence. We will get to these prospects in later chapters. In the next and succeeding sections, we will address the recalcitrant nature of cancer and how it emerges and disseminates as part of metastatic spread.

Turning winners and losers

Tissues and organs are crowded with millions of cells that have to maintain the dictates of their genetic programming so that they support tissue function. But gene mutations occur and are actually quite common. Immune functioning undoubtedly plays a pivotal role in diminishing cancer occurrence, but some nonimmune cellular mechanisms also act in a protective capacity. Indeed, ordinary cells may compete with mutated cells for dominance, and in so doing may eliminate precancerous cells that could eventually evolve into cancer. They may do so through the promotion of apoptosis (programmed cell death), pushing cancer cells out of tissues, or by engulfing and cannibalizing them (autophagy). These cells act as a group, and when one of their number seems not to be doing what it was meant to do, it is banished by the group (considered a black sheep). Eliminating these cells—which we can call loser cells—is adaptive in that resources that would otherwise have been lost to them will be conserved. And yet, cancers grow and tumors form: these are the mutations that have won. Winner cells continue to proliferate, reflecting a natural selection process to maximize cellular well-being. Some of these cells are supercompetitors, carrying mutations, such as the MYC or the Minute gene, or those that diminish p53 that ordinarily limits cell division, and that are especially effective in maintaining the fitness of the cell population (Dejosez et al., 2013). Such findings led to the obvious question as to whether groups of such cells could be harnessed to eliminate cancerous cells. This will require defining what constitutes an undesirable cell (or a loser cell) by the markers that it carries. Alternatively, if a cancer cell carries a winner marker, it could possibly be used as a target for destruction (Madan et al., 2019). Identifying these cells at very early stages, for example, by detecting mutations through RNA sequencing, may facilitate cancer prevention (Yizhak et al., 2019).

Treatment resistance

Even when cancer therapies seem to be having positive effects in reducing tumor size, it is not unusual for the efficacy of the treatment to diminish. The development of resistance to therapies is among the greatest problems encountered in effectively treating cancer. Drug resistance may involve processes in which individuals are inherently resistant to certain drugs (intrinsic resistance) or through acquired resistance that develops with continued exposure to specific treatments. Cancer cells are unstable so gene mutations occur frequently and become more common with the growth of the cancer. As the features of the cancer change, the effectiveness of treatments may wane, possibly owing to the activation of specific pathways that ordinarily act against toxicants, which can include drugs to fight cancer. The cancer cells may also carry mutations that limit the effects of therapeutics, and selection processes may also be at play so that those cancer cells that are inherently less sensitive to therapies will be more likely to survive the assault by anticancer agents, thus allowing for more such cells to multiply.

Acquired resistance to cancer treatments can develop through mutations of the genes within cancer cells, alterations of the tumor microenvironment that favors cancer cell survival, or the promotion of another oncogene that becomes the primary driver of the tumor. Early in the disease process, selection pressures placed on tumor cells by the attacking immune system may increase the propensity for tumor gene variants to occur. As a result, some cancer cells will have a greater capacity to escape and survive attacks by therapeutic agents and generating similarly resistant progeny (Russo et al., 2019). As cancer cells continue to multiply, they may lose some of their basic features, so it may become increasingly more difficult for the immune system to identify them as threats. In this context, considerable heterogeneity exists between cancer cells within a tumor (e.g., varying genetically and metabolically), making it difficult to destroy all of them with a single treatment. Once again, those cancer cells that survive may be key in the development of treatment resistance.

Changes can also occur in the expression of cancer-related genes (through epigenetic processes discussed in Chapter 4) so they become less responsive to therapeutic agents. Beyond the altered actions related to genetic processes, treatment resistance can emerge owing to increased drug inactivation (e.g., by endogenous substrates within the body) and it similarly appears that the efflux of anticancer drugs may increase (Vadlapatla et al., 2013). Moreover, enhanced DNA repair processes may occur so cancer cell damage created by chemotherapeutic agents can be reversed (Mansoori et al., 2017). Being voracious consumers of energy, it has also been maintained that processes related to variations of adenosine triphosphate (ATP), which is fundamental to generating energy within cells, are fundamental in cancer progression and the emergence of treatment resistance (Wang et al., 2019)—as we will see shortly when we discuss the Warburg effect.

Metastases

Each cancer is different in its own way, and some cancers are more treatable than others. Primary tumors are often manageable, although treatment resistance may develop, and disease recurrence is not uncommon. After treatment cancer stem cells may still be present, waiting for the opportunity to appear elsewhere in a more aggressive form. They are much more difficult to treat, and there are few ways to determine whether these stem cells are hanging about. Small numbers of these cells can be detected in culture but identifying them in the living organism is another issue entirely. Still, there have been indications that certain enzymes can be used to find stem cells that might develop into cancers.

Most cells in the body seem to know that they belong where they are and stay put. They are retained in the tissue or organ through genetic instructions and local intercellular signaling molecules, operating in a concerted manner to fulfill the functions of the organ. Cancer cells, in contrast, are not content to remain as part of the main tumor mass and can migrate to distant sites where a new colony of cells is established. Cancer cells also have an uncanny ability to get around so that cancer can spread to multiple organs. It had been thought at one time that cancer cells were oblivious to their environment, focusing instead on their multiplication. Based on analyses that combine evolutionary biology and artificial intelligence it was deduced that cancer cells are spatially aware of their surroundings so they can change their shape allowing them to get by obstacles they encounter in their travels and get