Haecceity: An Ontological Essay

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Mechanism explains breast cancer cell plasticity Jan 28, May 16, Mar 08, Researchers find way to better use current drugs to target cancer Jun 22, Apr 01, A success in cancer prevention is the reduction in sun exposure and resulting decline in skin cancer in Australia due to an advertising campaign introduced in and called Slip Slop Slap that aims to make sensible sun exposure the social norm Green et al.

Confounding similar efforts in the U. A number of human carcinogens were first identified as a result of the industrial revolution when workers were exposed to high levels of novel chemicals or sources of radiation, resulting in noticeably higher concentrations of cancers Siemiatycki et al.

These examples, combined with the fact that, in the U. While there is no doubt that they cause some fraction, it is still difficult to know how much. Epidemiological data suggest that it is less than one might suspect, since there was no sharp rise in overall cancer rates that followed the industrial revolution. However, if many pollutants each contributed to a small increase in cancer risk, it would be very difficult to detect by epidemiological analysis alone. The reason that no striking increase in cancer rates was detected may well be due to strong environmental and workplace protections that limit the exposure to industrial carcinogens in the general population as well as for industrial workers.

Industrial use of some cancer-inducing agents with clear causation mechanisms, such as asbestos, is now strictly controlled. However, residual contaminated hot spots remain; there are cases per year in the U. Together, clean air, water, and workplace regulations coupled with active surveillance for validated carcinogens help to reduce exposure to these and other highly validated agents. On the other hand, there are many chemicals used in industrial production, agriculture, and household items that have unknown consequences for, or an unquantified impact on, risk.

It is likely that at least some cancers arise from a number of these with thus potentially modifiable exposures. It is nevertheless challenging to definitively assign risk to environmental factors because typically doses of suspected agents are low, and cancers can arise years after the initial exposure.

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In addition, carcinogens act in different ways, with some providing initiating stimuli inducing mutation , others primarily acting as tumor promoters particularly in susceptible individuals discussed below , and some doing both. Current approaches to identifying additional sources of risk build on a large body of past work that has systematically analyzed evidence for the risk of specific carcinogens causing distinct types of human cancer Cogliano et al.

One effort is profiling old and new carcinogens based on 10 essential features, including the following attributes of an agent: 1 acts as an electrophile either directly or after metabolic activation, 2 is genotoxic, 3 alters DNA repair or causes genomic instability, 4 induces epigenetic alterations, 5 induces oxidative stress, 6 induces chronic inflammation, 7 is immunosuppressive, 8 modulates receptor-mediated effects, 9 causes immortalization, and 10 alters cell proliferation, cell death, or nutrient supply Smith et al.

These efforts are supported by next-generation sequencing NGS and other profiling approaches that allow assignment at a molecular level of profiles associated with risk. These approaches also incorporate data generated by genomic, transcriptomic, and proteomic analysis Cote et al.

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There has been tremendous progress in medical treatment of many chronic and acute diseases. In some cases, although treatments may ameliorate symptoms or actually be lifesaving in the short term, they can also increase the risk of some forms of cancer over the long term. Among the better studied examples, ionizing irradiation used as treatments for cancer increases the risk of secondary cancers of a number of distinct types, characterized by specific genomic signatures Behjati et al. Given the life-threatening nature of many cancers, the risk imposed by irradiation and many forms of chemotherapy cannot be avoided.

However, other forms of medication are elective and are associated with the potentially avoidable risk of either cancer or death due to cancer, although the quantification of this risk is challenging. The use of alternative medicines for cancer treatment falls in this category Johnson et al. Another source of risk may arise from the use of hormonal therapies, such as estrogen replacement therapy after menopause, where some cancers, such as breast and ovarian, are elevated with specific formulations of hormones, while risk of other life-threatening conditions, such as heart disease, is reduced Lobo In some cases, medications may interact; for example, several intriguing studies have shown that androgen regulates the DNA damage response, influencing response to IR Polkinghorn et al.

These findings raise the possibility that long-term use of androgen deprivation therapy ADT or the change in estrogen—androgen balance associated with obesity may potentially alter the risk of cancer-inducing mutations arising from exposure to mutagenic stimuli. Finally, given the long latency of cancer formation and the growing use of new potent medications targeting many distinct classes of cellular signaling protein over the past several decades, it is likely that some of these may be tumor-promoting. The dilution of signal across the general population will make it difficult to identify such risks with current information sources.

A complementary approach to cancer prevention is the use of drugs or vaccines to inhibit, reverse, or delay the onset or progression of cancer, informed from an understanding of the molecular mechanisms underlying initiation and progression of nonviral tumors. Since drugs may need to be taken for long periods of time by healthy individuals, they must have no or minimal side effects.

This field of research is still in its infancy, but several Food and Drug Administration FDA -approved agents lead to significant reductions in the incidence of specific types of cancer. These include the selective estrogen receptor modulators SERMs tamoxifen and raloxifene and aromatase inhibitors such as anastrozole, letrozole, and exemestane Cummings et al. None is without side effects, however, so use has to be weighed against individual cancer risk and the fact that early detection and improved treatment of early stage estrogen receptor-positive breast cancers has continued to advance.

Another promising potential agent for cancer prevention is the anti-diabetic drug metformin. Metformin activates AMPK, inducing muscles to take up glucose from the blood and thereby ultimately reducing insulin production. The drug has been widely used for diabetics and found safe. Following the recognition that AMPK is a critical target of regulation by the LKB1 tumor suppressor, investigators performed a retrospective review of clinical data that suggested that diabetic patients receiving metformin might have a reduced risk of cancer Evans et al. This initial study was supported by a number of others that reached similar conclusions Decensi et al.

Clinical trials are under way to determine the efficacy of this drug in preventing breast, colorectal, pancreatic, and prostate cancers Amin et al. A number of studies have investigated the impact of NSAIDs, including aspirin and COX-2 inhibitors, on the incidence, recurrence, and mortality from colon cancer. These agents can have significant preventive effects yet must be considered in the context of established side effects Gupta and Dubois ; Wang and Dubois ; Thompson et al.

As of , the U. Could nonviral cancers be prevented by vaccination? Dramatic success in immunotherapy for advanced cancers has invigorated the field. To date, target antigens have been largely patient- and tumor-specific. However, it is possible that common antigens for some types of cancers could be found. The decades-ago discovery that cancers often arise from and remain dependent on mutated oncogenes and tumor suppressor genes and that cells present peptides on their surface for screening by the immune system suggested that it might be possible to immunize against peptides bearing common mutations in cancer-associated genes, such as the tumor-promoting oncogene RAS or the tumor suppressor TP53 in this case, the target would be gain-of-function somatic mutations that act in a cancer-promoting manner.

That such mutations can be immunogenic in some major histocompatibility MHC contexts has been shown Tran et al. However, a vaccine comprised of multiple immunogenic peptides derived from KRAS showed promising activity in a mouse model of lung cancer Pan et al. When estimating cancer risk and developing strategies for prevention and early detection, it is important to consider that within a general population, the risk of individuals for specific types of cancer can vary significantly based on inherited factors.

Over the past two decades, the general understanding of factors causing genetic predisposition to cancer has increased significantly. The variants discovered in such studies were often highly penetrant forms of genetic variation strongly predisposing to cancer for a limited number of cancer sites.

For carriers of these variants, active surveillance starting at an early age, coupled in some cases with management of lifestyle exposures and prophylactic surgery e. It is now clear that such relatively common highly penetrant damaging genetic variants represent only a small subset of cancer-predisposing inherited variants. Indeed, the majority of risk-associated gene variants in an entire population is expected to be of low to intermediate penetrance. Many of these genes are dispersed across a network of proteins associated with control of the DNA damage machinery, directly targeting either proteins involved in DNA repair Srivas et al.

Some predisposing variants are associated with specific types of cancer and sensitivity to specific controllable factors; for instance, a variant in the BAP1 gene is predisposing to a small group of cancers, including mesothelioma Murali et al. Many variants of unknown significance VUSs occurring in the general population remain to be assigned for function. Ongoing efforts to characterize the import of such VUSs combine exome analysis and functional testing for phenotypic effects on DNA repair e. Large databases, such as ClinVar and others, are systematically compiling information found in affected individuals, the general population, and other populations of interest for example, the healthy elderly , with the goal of generating a resource that can be used to support statistical estimations of gene—risk correlation Bodian et al.

The NGS technological revolution has driven down the costs required to discover the complete set of genetic variants in large cohorts of individuals, allowing large surveys of variation in the exomes of cancer cases and associated population-based controls. Such studies may yield discoveries of rare forms of variation that confer intermediate and potentially actionable levels of risk; such forms of variation would have been missed by large-scale surveys of common variation. Aside from the daunting number of candidate cancer risk genes to be assessed, a number of confounding factors complicate risk prediction based on analysis of genes that function in an autocrine manner to prevent normal cells from undergoing transformation.

How tissue microenvironment versus cell-intrinsic factors restrains the transforming effect of these mutations remains to be established. In contrast to the longtime focus on cancer risk arising from inherited gene variants affecting the cell that becomes the tumor, a growing field of research addresses non-tumor-intrinsic inherited and noninherited features that influence the ability of a mutated cell to progress. Broadly speaking, these changes affect the tumor microenvironment—a compartment composed of multiple untransformed cell types, including both immune system and stromal cells, as well as secreted insoluble proteins of the ECM and associated soluble factors.

This vast topic cannot be summarized in any depth here for reviews, see Lu et al. We focus on two examples. A growing body of data indicates an important role for the host immune system in the surveillance and elimination of cancer cells, with the recognition that escape from immune restriction is an essential transition at early stages of tumor growth for review, see Dunn et al. This role for the immune system accounts for the well-known elevated rates of multiple forms of cancer in immunosuppressed patients, such as solid organ transplant recipients, where 32 distinct malignancies occur at elevated rates Engels et al.

In an exciting recent study, Marty et al. This led to the conclusions that some common drivers are uniformly poorly presented by MHC-1 alleles and also that there existed a strong correlation between an MHC-1 profile associated with poor presentation and the likelihood of the mutation being present in a patient's tumor.

This offers a new strategy to qualify the risk associated with specific inherited genetic variants or somatic mutations Marty et al. However, in assessing genetic contributions, it is also important to keep in mind the fact that immune system contributions can be potently influenced by the behavioral and environmental factors discussed above. As only one example, inflammatory signals associated with obesity alter the landscape of immune cells in a manner that promotes metastasis Quail et al.

Finally, the immune system is subject to declining or aberrant function in age e. The roles of stromal tissue and the ECM in regulating tissue and tumor growth have been long appreciated. In , Paget's proposal Paget ; for review, see Fidler ; Oskarsson et al. This influence of the ECM represents the contribution of both specific proteins present in the tumor microenvironment and also the overall architecture of the tissue matrix and degree of rigidity.

These contributions are highly relevant to all stages of cancer growth. For example, it is well established that mammographic density, which reflects ECM rigidity, is one of the strongest predictors of breast cancer risk Burton et al.

This density differs between distinct populations, being, for example, higher in Asian and lower in European women. The reasons for these differences are thought to involve height, weight, and parity Rajaram et al. However, regardless of the basal density of the mammary tissue, within genetically homogeneous populations, higher breast density is associated with greater cancer risk Bae and Kim These relationships clearly imply a role for breast density and ECM rigidity in creating a microenvironment that elevates the risk associated with any tumor-intrinsic initiating mutation.

Regional matrix stiffness is significantly increased as tumors begin to grow beyond microscopic precursor lesions, based on a feedback between nascent tumors and surrounding stromal cells that increases tension; these changes promote aggressive growth Paszek et al. As a further point of complexity, ECM rigidity varies dynamically over the life span, influenced by secreted signals from the senescent cells that accumulate in aging individuals Lecot et al.

The idea that cancer risk can be reduced based on modification of behavior or the environment or screening for specific risk-associated mutations is predicated on the idea that these factors are major or predominant contributors to the absolute incidence of cancer. However, an opposing viewpoint is that the major source of cancer risk is biologically programmed and cannot be avoided. This idea is based on the relationship between three key observations. It has long been known that some organ systems are more prone to cancer than others.

It has also been long known that some organ systems have a greater regenerative capacity than others, based on increased proliferative potential of individual cells. Finally, cancer risk correlates with age. The significance of the relationship between proliferation rate, organ specificity of cancer risk, and aging has been discussed for more than a century for review, see Goss ; Tomatis The idea linking these observations is that specific organs undergo replicative replacement throughout the life span of an individual, and this replacement process is marked by an unavoidable error rate, resulting in the gradual acquisition of sets of cancer-promoting mutations Armitage and Doll ; Knudson Adding relevance to this otherwise philosophical debate is that if a stochastic process is the major driver of cancer risk, the rationale and motivation for devoting significant efforts to prevention are undercut; in contrast, if biological programming is a minor risk factor or can be modified, prevention is strongly justified.

In a highly provocative report, Tomasetti and Vogelstein used a statistical approach to correlate available information about the stem cell complement of individual tissues in 31 distinct tissue types to estimate the total number of stem cell divisions possible for that organ type and then plotted the results against age of incidence for cancers affecting each of the tissue types for all tumors reported in the U.

They then defined an extra risk score ERS as a measurement of overall cancer risk across a lifetime. This latter group included lung cancer in smokers, cancers associated with HCV or HPV infection, and gastrointestinal tumors associated with hereditary mutations. In a follow-up study, Tomasetti et al. Although finding trends similar to those in their earlier analysis, this more comprehensive study led to a more nuanced conclusion, maintaining the emphasis on replicative effects for many tumors but also noting that, for certain tumor types, environment made a major contribution.

The arrival of high-throughput sequencing techniques, making large numbers of cancer genomes available for inspection, allows a reformulation of this debate in molecular terms. Alexandrov and colleagues Alexandrov et al. The initial study, analyzing 4,, mutations from cancers, identified 20 distinct signatures, of which a subset was associated with the age of the patient at cancer diagnosis.

This expanded analysis now identified 33 mutational signatures. For two of these signatures nos. Cancer types marked by this signature included stomach, colorectal, glioblastoma, esophagus, medulloblastoma, and pancreatic, which include several tissue types associated with high replication rates, in accord with the idea that replication-associated defects are particularly relevant in these tumors. Signature 1 appears to be associated with deamination of 5-methylcytosine at CpG dinucleotides, which causes T:G mismatches that are not effectively repaired at replication.

The investigators hypothesize that the specific elevation of signature 5 in specific kidney tumor types may reflect exposure to a metabolism-associated mutagen abundant in renal tissue, but the mechanism is currently unclear. Both of these age-associated signatures are present at a relatively low level in other common cancers, including breast, melanoma, ovarian, and AML. Furthermore, the fact that even the two aging-associated signatures do not correlate with each other suggests the involvement of some tissue-specific component exclusive of aging.

This suggests that, for these sources, the contribution of replicative effects replication error is low and that most of the risk is associated with either hereditary or environmental effects. Although it is likely that further genes associated with hereditary risk will emerge, this pattern suggests a potentially large contribution of environmental factors and a similarly large role for prevention.

Another intriguing observation that suggests the importance of modifiable environmental factors is the fact that, even for tumors where there is currently strong evidence for a correlation between abundant stem cell population, high replicative potential, and an age-associated signature of mutations, the pattern of tumor incidence is changing in the general population. For example, while the incidence of colorectal cancer is decreasing overall in the U. Such an observation is difficult to explain solely through a stochastic model based on stem cell pools unless one assumes that the size of the stem cell pool is itself affected by factors such as environmental toxins and obesity.

This is not inconceivable; a number of proteins that support stem cell self-renewal potential have been shown to be up-regulated and promote aggressive tumor aggressiveness in cancers e. Furthermore, as deep genome analysis now begins to address clonality as a critical feature of the emergence of tumors, it is becoming recognized that mutational patterns within a single tumor mass—or even within morphologically normal tissue—can be highly complex, creating uncertainty about absolute mutation rates Cooper et al.

Deep comprehensive molecular surveys of tumor genomes are an emerging field; ultimately, the ability to compare the mutational spectrum and incidence patterns of tumors diagnosed over multiple decades should definitively inform this debate. At present, the sum of the data available supports the idea of an important role for environmental and behavioral contribution to cancer risk.

While multistep models may explain the dramatic increase in cancer incidence with age, they do not preclude the possibility that complex and potentially reversible aging-related processes might contribute to cancer through systemic changes that favor tumor growth Campisi , These aging-related changes may differ from organ to organ and can include diverse processes such as impaired immune response, defects in DNA repair, and altered hormonal environment. As data in support of this idea, mutations that extend life span in mice delay the onset of diseases of old age, including cancer.

Furthermore, senescent cells that accumulate with age secrete factors that can be inflammatory, can promote angiogenesis, and can favor the growth of cancer in mouse models Campisi In the immune system, the phenomenon of age-related clone hematopoiesis ARCH , also known as age-related clonal expansion, describes the reduction in clonal diversity among hematopoietic stem and progenitor cells that gradually reduces the functionality of the immune system Shlush The molecular basis for ARCH is unclear but is likely to represent a combination of cell-intrinsic mutations and microenvironmental effects; individuals with ARCH are at higher risk for some forms of cancer, including nonhematological cancers Forsberg et al.

Hence, this aging-related deficiency may be at least partially controllable through prevention methods. Such observations have stimulated efforts by companies to develop drugs to prevent cancer by delaying aging itself or at least eliminate aged cell populations. Similar senolytic effects were seen for other targeted therapies, including dasatinib, HSP90 inhibitors, and other agents Zhu et al. Cancer 5-yr survival rates vary substantially between anatomic sites and depend on the size, grade, and stage of the tumor.

Stage refers to whether the tumor is local confined to the organ of origin or has metastasized regionally has extended beyond the organ of origin to surrounding tissues or lymph nodes or distantly to remote tissues. For all tumors, 5-yr survival rates are best if the tumor is detected at the local stage, although, for some tumors, even early detection is associated with poor survival because of the current lack of effective treatment strategies.

Thus, a major means of lowering cancer mortality for many cancers is to detect them at the local or even regional stage and treat them promptly. For many cancers detected at the local stage, surgical resection may be the only treatment recommended and may be curative. The chief means of early detection for many cancers is the recognition by the patient that something is awry following the appearance of characteristic signs or symptoms e. This awareness alone, combined with increased access to health care or the means to pay for it such as Medicare and Medicaid, in the U.

A broad portfolio of evidence-based tests proven to reduce cancer-associated mortality and suitable for application in large populations is currently available to screen for cancer.

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Additional options ranging from classic medical approaches to new tests based on molecular signatures and other recently established biomarkers are in development. Methods for population testing include fecal occult blood or immunochemical screening or endoscopy of the lower gastrointestinal tract colorectal cancer , visual inspection of the cervix or cytology cervical cancer , detection of an oncogenic virus e.

These screens fall into two fundamental classes: those that identify premalignant lesions and remove the damaged tissue e. Notably, there are multiple options for some types of cancer, such as breast, colorectal, lung, and cervical cancers, which account for a high proportion of cancers globally. However, there are no feasible options available to screen at the population level for most other types of cancer, highlighting an area where investment in test development might lead to major public health dividends.

Also notable is that the equipment and expertise needed to screen varies substantially according to the organ site, and thus screening programs tend to be site-specific, and there are few economies of scale across sites. Screening tests are generally evaluated in terms of their sensitivity the percent of true disease positives, who are called as positive by the screen and their specificity the percent of true disease negatives, who are called as negative by the screen.

In general, sensitivity needs to be high e. Specificity needs to be even higher e.

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This is in part so that the proportion of true negatives i. Also, at a population level, high specificity is important so that the health system is not overwhelmed by expensive and unjustified follow-up testing although here the specificity requirement depends on whether the consequences of being labeled positive are relatively minor [e. Another key performance characteristic is the positive predictive value PPV ; i. A good screening test will have a high PPV. An important fact about this metric that is not necessarily intuitively understood is that the PPV of a test varies with the prevalence of the disease being tested for.

Thus, the PPV varies according to whether the disease is rare or common in the population screened; the rarer the disease is in the population, the higher the fraction of test positives who are false positives will be. This obviously has implications for test development for cancers that are relatively common e. A technically excellent screening test is no use if it is 1 too expensive to justify, 2 needs to be repeated too frequently to be feasible, 3 takes too long to generate a result, 4 identifies cancers at such a late stage that treatments are ineffective, 5 or is followed by confirmatory tests that do more harm than good or 6 if people cannot be convinced that they should be screened with the test.

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Thus, the development of a cancer-screening program involves many actors—the government or insurance companies, the people administering the test and following up the results, and the population being tested being prepared to submit to the test. Because the characteristics of each screening test are different and vary according to the population being screened and the level of development of the health system, no cancer-screening test is universally applied worldwide.

One of the most successful screening tests has been the Papanicolaou Pap smear for prevention of cervical cancer. In this test, cells are collected from the opening of the cervix and stained with a mixture of five dyes selected to highlight cellular features, including the keratins found in squamous cell carcinomas. Cervical cancer mortality in the U.

By detecting both premalignant and malignant lesions, the Pap smear both reduces the risk of cancer by leading to the removal of premalignant tissues, which are scraped off by colposcopy subsequent to an abnormal test result, and reduces risk of cancer mortality by leading to early diagnosis of curable cancers. In many less developed countries, however, efforts to introduce the Pap smear have failed, due in part to the time it takes to get an answer usually the slides are sent to a central laboratory for microscopy, by which time the patient may not be available for follow-up colposcopy.

Other issues include the difficulty of getting results back to women who may not have a telephone, postal service, or other means of communication; high costs; the requirement for skilled personnel for interpretation of results; and the lack of personnel for follow-up treatment of positive or suspicious smears as surgeons and operating theaters may ultimately be needed if a cervical amputation or hysterectomy is required.

Fortunately, developments in molecular biology have enabled advances in cervical cancer prevention and screening in two ways. The finding that oncogenic strains of HPV are a necessary cause of cervical cancer Walboomers et al. The two first developed and commercially available vaccines Gardisil and Cervarix were virus-like particles VLPs based on expression of the major L1 capsid protein derived from multiple oncogenic HPV strains.

A current challenge is extending the use of the vaccine, including to young men as well as young women, which is particularly important given the rapidly growing incidence of cancers at noncervical anatomical sites, such as the head and neck Chaturvedi et al. Screening techniques have also improved based on exploitation of the obligate infection of the cervix with high-risk HPV strains prior to detectable Pap abnormalities. Colorectal cancer is the second leading cause of death in the U. Preventive Services Task Force Early detection has a huge impact on preventing death from this disease, and fuller uptake of proven methods of early detection represents an opportunity to realize large gains from population-level screening.

The gold standard method of screening for colon cancer for the past several decades has been by colonoscopy, with a standard recommendation of commencing such testing at age 50 and then testing every 10 yr for members of the general population lacking known risk factors. For individuals with known hereditary risk factors for colorectal cancer e. Preventive Services Task Force ; Knudsen et al. Comparative assessments of these tests have indicated that for the general population, colonoscopy every 10 yr, annual FIT, sigmoidoscopy every 10 yr with annual FIT, and CoTCo every 5 yr yielded similar benefits in improving life span if the tests are applied between the ages of 50 and The fact that noninvasive FOBT testing is performing so well suggests that this type of testing may be more readily adopted by individuals unwilling to undergo more invasive screening approaches.

Although mammography has become established as a means to reduce breast cancer mortality, the data regarding the value of this approach to prevention are surprisingly controversial, with large disagreement on the extent of any reduction in mortality. However, this may come at a price of overdiagnosis of breast cancers i. The original rationale for mammography at the population level has been the idea that tumor progression goes through a set progression, where tumors reach a minimal size that is detectable by mammography before metastasis occurs.

This paradigm has been challenged by a number of recent studies using genomic analysis, analysis of circulating tumor cells discussed below , and sophisticated imaging techniques to analyze the timing of tumor dispersion. Emerging data suggest that early stage tumors secrete small extracellular vesicles that condition niches to enhance the growth of metastasizing cancer cells Peinado et al. Similar early dissemination has been seen for other solid tumor types, such as pancreatic tumors Rhim et al. Further studies of pancreatic cancer have suggested that such metastases may arise from clonal populations within the larger tumor mass, further uncoupling measurement of tumor size from propensity to metastasize Yachida et al.

This evolving understanding of metastasis Massague and Obenauf supports the idea that prevention approaches focusing on detection and genomic characterization of circulating tumor cells in the peripheral blood may significantly augment mammography in limiting breast cancer mortality for instance, if effective interception strategies are developed that can control the establishment of metastases before primary tumors are detectable by imaging. A highly contentious screening test is regular testing of men for PSA in order to detect prostate cancer.

PSA screening, which became popular in the U. In , the U. Preventive Services Task Force The results of randomized trials of screening compared with usual care have been much debated, with many men in the nonscreening arm of the major U. The most solid conclusions are about the difficulty of doing randomized trials of a screening method that has achieved broad popularity. There is no doubt that PSA testing results in the detection of lesions that pathologists label as cancer in a high proportion of men. Problems with this test include the fact that heterogeneity of prostate cancer aggressiveness among individuals makes it difficult to predict which individuals will develop a life-threatening disease.

Blood-based tests such as PSA screening start with the advantage that the initial screening test does not require expensive equipment such as spiral CT machines for lung cancer screening , unpleasant preparation such as the bowel prep for colonoscopy , exposure to radiation such as mammography , or clinical skills such as the Pap smear.

Thus, there is enthusiasm for the concept that finding tumor markers in the blood may provide a method of routinely screening large populations and potentially replace some of the more burdensome methods Aravanis et al. The sensitivity of these tests may be limited by the fact that most cell-free DNA is derived from normal cells, and the specificity may be limited by the fact that cancer-associated mutations increase with age in tissues that are not yet cancerous Bardelli and Pantel Other liquid biopsies focus on the analysis of extracellular vesicles EVs; comprising exosomes, microvesicles, and oncosomes : small membrane-encased vesicles shed from normal and tumor cells that can transfer nucleic acids and proteins between cells Strotman and Linder EVs derived from tumors have attracted great interest, based on evidence that they can perform functions ranging from conditioning the premetastatic niche to immune suppression to control of angiogenesis Sato and Weaver Such testing is likely to become routine for some cancers, although the hurdles to converting this information into a test for early detection that could be applied to individuals in the general population remain high.

It will be imperative to develop more selective and efficient capture techniques, incorporate advances in bioinformatics and computation, and obtain greater insights and context from cancer biology to further research in this high-priority area of cancer prevention see also Lewis et al. To explore the extent of a maximal impact of prevention through uptake of idealized health-promoting behaviors and policies, we examined two recent studies that quantified these effects Kohler et al.

Kohler et al. From this information, they were able to estimate resulting preventable cancers and deaths. Islami et al. Notably, the two studies were roughly concordant in their findings, notwithstanding their differing methodologies. This concordance strengthened their conclusions and emphasized the promise of primary prevention in limiting cancer incidence, highlighting the potential of idealized population-wide adherence to recommended healthy behaviors and implementation of policies that reduce cancer risk.

For convenience, we focus on the recent study by Islami et al.

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Risk factors were obtained by a meta-analysis of multiple published studies to identify modifiable risk factors for which a causative role in cancer is supported by sufficient or strong evidence. Cancer incidence in the U.

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These data were analyzed in the context of age- and sex-specific risk factor exposures to estimate PAFs; PAFs were then summarized by cancer site and risk factor as well as in aggregate. Figure 6 is an alternative presentation of findings from Islami et al. Several observations jump out. First, the burden of cancer deaths of the lungs and part of the aero—digestive tract organs heavily exposed to tobacco in smokers is exceedingly high even compared with cancer deaths in other common cancer sites, such as the colorectum, breast, and pancreas.

Second, these lung cancers reside high in the plot, illustrating that they are largely preventable—at once sobering and motivational. Cancer deaths attributed to modifiable risks. Each anatomically categorized cancer was plotted by the current annual deaths due to that cancer X -axis; total deaths in and the proportion of deaths attributable and thus preventable by the elimination of risk factors to the following modifiable risk factors: tobacco, UV exposure, infections, and Western lifestyle Y -axis; PAF.

Cancers i. Cancers shown in the top left result in far fewer cancer-associated deaths but may be similarly profoundly reduced through population-wide adoption of healthy behaviors and policies e. This figure was plotted based on data from Tables 2 and 4 of Islami et al. We note that our presentation, as with Islami et al. Prostate cancer, for example, is omitted.

For attributable cancer cases data not shown , a figure emerges that is similar to that for deaths. If considering only cancer incidence, colorectal and breast are shifted far to the right, with the large number of annual breast cancer diagnoses exceeding even those for lung cancer. The relatively lower mortality for these cancers reflects reductions achieved through treatment, early detection, and screening. The high ratio of cases to deaths for UV exposure is likely due to melanoma being amenable to earlier detection and a resulting relatively favorable survival.

Annual estimates of U. There exist caveats to these estimates, as acknowledged by Islami et al. Risk factors were assumed to influence cancers independently not interacting and without correlative effects among cancers. This does not necessarily fully reflect what is known in cancer biology based on emerging evidence about the interaction of risk factors, as summarized above. We also note that the inclusion of only established effects and the incomplete nature of data in cancer registries lead to an underestimate of the total number of cancer deaths attributable to these factors.

Due to the specific choice of cancers and risk factors considered in this analysis, the number of deaths that we estimated as avoidable by primary prevention is an underestimate and should thus be considered as a lower bound. We also note that the risk factor exposure estimates were from the most recent year available and thus not averaged over the lifetime of cases, the data for which were also measured in a single time point i.

While Islami et al. Since the war on cancer began, there have been continual improvements in survival from many cancers thanks to advances in imaging, surgery, radiation, chemotherapy, and a handful of adjuvant therapies such as tamoxifen.

CrossFit | Fasting and Cancer: Molecular Mechanisms and Clinical Applications

In parallel, there have long been significant efforts to develop resources in education and infrastructure to support screening and prevention behaviors in the general population Engstrom ; Amsel et al. Today, thanks to stunning research progress that has led to a much better understanding of the biology and genetics of cancer, immunotherapy and some targeted therapies promise additional improvements in treatment outcomes over the next 20—30 yr. Such advances also raise the possibility that, with further research, some cancers might be prevented or treated successfully at very early stages by drugs or vaccines.

Despite such success, it is probably fair to say that only by the broader use of proven methods of prevention and early detection, together with treatment, can one guarantee major reductions in current U. The fuller uptake of existing methods of prevention and early detection across the U. A meaningful discussion of this topic is beyond the scope of this review. For example, it is now well established in the cancer prevention community that the adverse impact of low SES on prevention is multidimensional and significant. Therefore, they have more opportunities to be infected with cancer-associated microbes, fail to undergo recommended screening, and experience delays in diagnoses associated with later stages of disease at presentation , all of which contribute to poor outcomes.

For these reasons, effective prevention will require much more than public education on the topic; indeed, most of the potential gains would require actions by governments or large social movements. As a starting point, the interested reader is directed to the following works, and references therein: Colditz and Wei , Stringhini et al. However, for the molecular biology community, the topics in this review suggest some areas for productive research.

For example, better understanding of critical carcinogenic effects of agents such as obesity, alcohol, and processed meats may lead to the development of targeted interventions that detoxify proximal mutagens and cancer promoters. Better understanding of the mechanism of immune surveillance in cancer may improve cancer vaccines in a manner tailored for individuals with distinct MHC haplotypes.

Better understanding of the specific ways in which senescent cells negatively condition the tumor microenvironment may lead to prophylactic interventions that either eliminate specific senescent cell populations or blockade their negative effectors. Microfluidic capture approaches continue to enhance the process of early detection. With an ever clearer view of the mechanistic underpinnings of cancer risk, it becomes more possible to develop tools to counteract these processes, improving quality of life and survival.

We thank Anthony San Lucas for assistance with the figure on preventable cancers. We thank Ruthann Rudel for valuable input on environmental carcinogens. The authors were supported by R01 DK to E. Anderson Cancer Center. Article published online ahead of print. View all Molecular mechanisms of the preventable causes of cancer in the United States Erica A.

Golemis 1 , Paul Scheet 2 , Tim N. Beck 1 , 3 , Eward M. Scolnick 4 , David J. Previous Section Next Section. Surprising discoveries from cancer epidemiology In theory, the majority of cancers may be preventable It has been known for nearly yr that at least some cancers are caused by environmental, occupational, or behavioral exposures, scrotal cancer in chimney sweeps being a famous early example Pott ; excerpted in National Cancer Institute A small number of carcinogens cause a surprisingly large fraction of U.

Major U. Figure 1. Mechanisms of carcinogenesis The molecular basis for the carcinogenicity of smoke has been analyzed in detail Hecht ; Joehanes et al. Figure 2. Successes and failures in eliminating cigarette smoking The reduction in U. Figure 3. Viruses and bacteria When the war on cancer began, many suspected that viruses would prove to be a major cause of human cancers.

HPVs: identification and mechanisms of carcinogenesis and elimination The initial recognition that HPV infection was associated with early stages of cervical cancer formation was made in Meisels and Fortin ; zur Hausen Figure 4. Lifestyle factors: identification and mechanisms of carcinogenesis and elimination A group of cancer risk factors that includes obesity, diet, and physical inactivity was first identified in affluent industrialized countries and is seen increasingly in populations around the world. Obesity Obesity typically arises when the intake of calories exceeds metabolic needs for tissue homeostasis over long periods of time.

Figure 5. Diet In addition to excess calories, many individuals consume a diet that includes high levels of meat and carbohydrates but fewer fruits, legumes, and vegetables. Physical inactivity Diet is linked to obesity, and diet and obesity increase cancer risk.

Sun exposure: identification, mechanisms of carcinogenesis, and reducing exposure Approximately , melanomas will be diagnosed in the U. Additional causes of cancer in the U. Medical care There has been tremendous progress in medical treatment of many chronic and acute diseases. Molecular prevention, interception, and immunization against nonviral cancers A complementary approach to cancer prevention is the use of drugs or vaccines to inhibit, reverse, or delay the onset or progression of cancer, informed from an understanding of the molecular mechanisms underlying initiation and progression of nonviral tumors.

Inherited risk factors affecting tumor initiation When estimating cancer risk and developing strategies for prevention and early detection, it is important to consider that within a general population, the risk of individuals for specific types of cancer can vary significantly based on inherited factors. Non-cell-autonomous inherited and acquired traits influencing tumor formation In contrast to the longtime focus on cancer risk arising from inherited gene variants affecting the cell that becomes the tumor, a growing field of research addresses non-tumor-intrinsic inherited and noninherited features that influence the ability of a mutated cell to progress.

Immune surveillance A growing body of data indicates an important role for the host immune system in the surveillance and elimination of cancer cells, with the recognition that escape from immune restriction is an essential transition at early stages of tumor growth for review, see Dunn et al. Population screening tests for cancer The chief means of early detection for many cancers is the recognition by the patient that something is awry following the appearance of characteristic signs or symptoms e. Types of tests A broad portfolio of evidence-based tests proven to reduce cancer-associated mortality and suitable for application in large populations is currently available to screen for cancer.

Technical performance of a screening test Screening tests are generally evaluated in terms of their sensitivity the percent of true disease positives, who are called as positive by the screen and their specificity the percent of true disease negatives, who are called as negative by the screen.

Programmatic performance of a screening test A technically excellent screening test is no use if it is 1 too expensive to justify, 2 needs to be repeated too frequently to be feasible, 3 takes too long to generate a result, 4 identifies cancers at such a late stage that treatments are ineffective, 5 or is followed by confirmatory tests that do more harm than good or 6 if people cannot be convinced that they should be screened with the test.

Early detection methods in the U. Colonoscopy and other tests for colon cancer Colorectal cancer is the second leading cause of death in the U. Mammography Although mammography has become established as a means to reduce breast cancer mortality, the data regarding the value of this approach to prevention are surprisingly controversial, with large disagreement on the extent of any reduction in mortality. Figure 6. View this table: In this window In a new window.

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