Molecular mechanisms of the preventable causes of cancer in the United States

Abstract

Annually, there are 1.6 million new cases of cancer and nearly 600,000 cancer deaths in the United States alone. The public health burden associated with these numbers has motivated enormous research efforts into understanding the root causes of cancer. These efforts have led to the recognition that between 40% and 45% of cancers are associated with preventable risk factors and, importantly, have identified specific molecular mechanisms by which these exposures modify human physiology to induce or promote cancer. The increasingly refined knowledge of these mechanisms, which we summarize here, emphasizes the need for greater efforts toward primary cancer prevention through mitigation of modifiable risk factors. It also suggests exploitable avenues for improved secondary prevention (which includes the development of therapeutics designed for cancer interception and enhanced techniques for noninvasive screening and early detection) based on detailed knowledge of early neoplastic pathobiology. Such efforts would complement the current emphasis on the development of therapeutic approaches to treat established cancers and are likely to result in far greater gains in reducing morbidity and mortality.

Keywords: cancer mechanisms; cancer prevention; early detection.

Figure 1.

Trends in tobacco use and lung cancer death rates in the U.S. Per capita cigarette consumption versus lung cancer death rates for men and women in the U.S. The figure is reproduced with permission from Cancer Risk Factors and Screening 2018 (https://www.cancer.org/research/cancer-facts-statistics.html), a presentation from the American Cancer Society (American Cancer Society. Cancer Prevention and Early Detection Facts and Figures 2018. Atlanta: American Cancer Society, Inc.). Note that rates are age-adjusted to the 2000 U.S. standard population. Data for death rates are from U.S. Mortality volumes 1930–1959, Mortality Data 1960–2015, National Center for Health Statistics, and Centers for Disease Control and Prevention (https://www.cdc.gov/nchs/products/vsus.htm). Data for cigarette consumption 1900–1999 are from U.S. Department of Agriculture 2000–2015 (Wang et al. 2016).

Figure 2.

Molecular and cellular responses to tobacco smoke. (A) Tobacco smoke contains >70 classified carcinogens (Hecht and Szabo 2014); shown are five compounds strongly associated with mutagenesis: benzo(a)pyrene (BaP), nicotine-derived NNK, N-nitrosodimethylamine (NDMA), 4-aminobiphenyl (4-ABP), and N-nitrosonornicotine (NNN). Many of the compounds in tobacco smoke are metabolized by cytochrome P450, resulting in molecules with highly reactive electrophilic moieties. (Black bar) Representative molecular structures with electrophilic moieties produced from the chemicals metabolized by P450. Electrophilic moieties can readily interact with DNA to form DNA adducts. DNA adducts can be repaired to correct the obstacle and re-establish “normal” DNA; this is frequently achieved by the cell's repair machinery through a process called nucleotide excision repair (NER). However, if repair is unsuccessful and cells do not undergo apoptosis, permanent procancerous mutations may be established. (B) Epigenetic modification commonly refers to processes that do not directly alter genetic information encoded by DNA but rather alter availability of genes for transcription; for instance, by addition of reversible methyl or acetyl modifications to DNA or histones. Chronic exposure to tobacco smoke extensively modifies the epigenome of cells in the affected tissue, with characteristic modifications, including hypermethylation of CpG islands (regions with high occurrence of cytosine and guanine separated by only one phosphate group, frequently found near gene promotors). This hypermethylation, generally in the context of tobacco-induced mutations, leads to reduced expression of genes important for tumor suppression and has been shown to significantly contribute to lung tumor formation (Vaz et al. 2017). Methylated residues (filled black circles) are typically generated by the action of methyltransferase enzymes (e.g., DNMT1 and EZH2) and limit transcription of growth inhibitory proteins. (C) Tobacco smoke also induces an inflammatory response that involves both epithelial and immune cells. Chemicals in the smoke induce production of fibrosis-associated proteins, most prominently TGF-β (transforming growth factor β); a number of highly active cytokines and regulators of the immune system (e.g., IL-8, C-X-C motif chemokine proteins [CXC], TNF-α, and others); and the release of nitric oxide (NO). This induces fibrosis and remodeling of the extracellular matrix (ECM), creating a more favorable microenvironment for tumorigenesis. (MMPs) Matrix metalloproteinases; (LTB4) leukotriene B4.

Figure 3.

Trends in lung cancer incidence in California and Surveillance, Epidemiology, and End Results (SEER) (SEER) areas other than California, 1988–2012. The age-adjusted incidence of lung cancer in California versus in areas of SEER data other than California. The greater decline in incidence in California correlates with strong anti-smoking policies that have led to lower rates of cigarette smoking in California than in most other parts of the U.S. The figure is taken from California Facts and Figures 2016 (http://www.ccrcal.org/pdf/Reports/ACS_2016_FF.pdf). Note that rates are age-adjusted to the 2000 U.S. population. Data are from the American Cancer Society, California Department of Public Health, and California Cancer Registry. Data for Oakland, California, are from American Cancer Society, Inc., California Division, 2016 (https://www.cdph.ca.gov/Programs/CCDPHP/DCDIC/CDSRB/Pages/California-Cancer-Registry.aspx).

Figure 4.

HPV, HBV, and HCV induction of cancers; molecular pathways. (A, left) In normally growing cells, the action of two tumor suppressors, p53 and RB, is critical in timing the cell cycle and limiting cell growth. p53 activity involves induction of growth inhibitory proteins such as p21/CDKN1A, which inhibits CDK2/Cyclin E and direct DNA binding and transcription; RB sequesters the essential S-phase-promoting transcription factor E2F. Timed inhibition of p53 and RB activity allows progression beyond G1. (Right) During chronic infection, HPV integrates its genomic material into the genomic material of human cells, allowing production of viral proteins. Two HPV-associated proteins critical for cell transformation are E6 and E7, which disrupt the core machinery that regulates cell cycle progression. E6 binds to E6–AP to promote the degradation of the tumor suppressor p53. E7 directly targets and disrupts the function of RB and related proteins, causing the release of E2F transcription factors, which promote transition to S phase and thereby drive cell proliferation. Some reports also suggest that E6 and E7 disrupt the inhibitory activity of p21 on CycE–CDK2 in a p53-independent manner. Notably, low RB levels correlate with an increase in the p16/CDKN2A growth inhibitory protein, commonly used as a biomarker to diagnose HPV-positive cancers; however, this does not result in cell cycle block because of additional genomic changes in HPV-positive cancers, such as elevated expression of Cyclin D. (B) Infection with HBV and HCV is a common cause of hepatocellular carcinoma (HCC). The percentage of cases in which the virus is not cleared adequately by the immune system varies greatly between HBV (5%–10%) and HCV (85%), with a subset of chronic cases progressing to hepatitis, cirrhosis, and eventual development of HCC. Hepatitis D virus (HDV) requires HBV coinfection but increases the risk of cancer in cases where the viruses are coincident. (C) During carcinogenesis, HBV regulatory X protein (HBx) and the HCV NS3, NS5A, and other core proteins activate prosurvival proproliferation receptors (insulin-like growth factor 1 receptor [IGF1R] and ERBB2) and downstream signaling pathways (RAS–ERK and PI3K–AKT). Furthermore, infected cells experience elevated levels of mitochondrial stress and endoplasmic reticulum (ER) stress (Wallace 2012; Clarke et al. 2014). Integration of HBV also induces transcription of important regulatory genes, including MLL, ARID genes, TERT (telomerase reverse transcriptase), and CCNE1 (CycE). HBV and HCV infection has also been shown to repress p53 expression and, in the case of HCV, RB. YAP, an important oncogene frequently elevated in HCC, has been linked to HBx.

Figure 5.

Cancer related molecular mechanisms driven by obesity. (A) Obesity causes formation of an expanded compartment of fat-storing cells (adipocytes) and accumulation and activation of immune cells. Signaling from these cells is commonly associated with an increase in TNF-α and IL-6 activity, two important regulators of cell proliferation and inflammation, and is related to immune cell activation. Obesity is also associated with an increase in the level of hormones, such as estrogen, insulin, and leptin, and a decrease in adiponectin, an important negative regulator of metabolism. (B) Excess adipocyte activity increases levels of bioavailable testosterone (T) and estradiol (E2) throughout the body. Within adipocytes, androstenedione (Δ-4A) is modified to testosterone by 17β-hydroxysteroid dehydrogenases (17β-HSD) or to estrone (E1) by aromatase (an enzyme also known as estrogen synthetase). In obesity, elevated aromatase expression is facilitated in part by increased levels of prostaglandin (PGE₂) and TNF-α. In certain tissues (e.g., breast and endometrium), high levels of testosterone and estradiol have been associated with cancer growth and survival. (C) Obesity elevates levels of insulin and IGF1, which bind receptors (INSR and IGF1R) expressed on tumor cells to activate core signaling cascades mediated by RAS and PI3K–AKT–MTOR that strongly drive cell proliferation and survival. (D) In the obese state, low levels of adiponectin reduce activity of AMP kinase (AMPK), a strong regulator of metabolic activity, particularly relevant in terms of the regulation of MTOR. At low levels of adiponectin, MTOR activity contributes to increased cell proliferation, anti-apoptotic activity, and expression of prometastatic genes. Adipocyte-produced leptin and immune cell-produced IL-6 activate JAK–STAT3 signaling to promote cell proliferation and survival. TNF-α inhibits the negative NF-kB regulator IkB, freeing NF-kB to further support a progrowth state.

Figure 6.

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 2014) 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). Circle size is in proportion to cancer-specific incidence (incident cases, 2014), and colors are assigned by SEER 5-yr relative survival estimates (2007–2013; https://seer.cancer.gov/statfacts). Thus, although cancers of the breast and pancreas situate proximally, indicating an approximately equal number of total deaths and a similar PAF for the examined risk factors, breast cancer incidence is much higher (larger point size), and outcomes for breast cancer are far superior (bluish purple in color, indicating a >75% relative survival). Cancers (i.e., lung) shown in the top right are those for which we can achieve the greatest reduction in total cancer deaths by the population-wide adoption of healthy behaviors and policies, such as tobacco prevention/cessation or elimination. 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.g., avoiding tobacco, cancer-associated infections, and harmful UV exposure). This figure was plotted based on data from Tables 2 and 4 of Islami et al. (2017) and from SEER (https://seer.cancer.gov/statfacts).