In a recent review published in the Cell Journal, researchers reviewed existing data on tumor-promotive risk factors and their underlying mechanisms.
Study: Impact of risk factors on early cancer evolution. Image Credit: Shamleen/Shutterstock.com
Background
Cancer may arise due to intrinsic or non-intrinsic (cell-extrinsic and exogenous risk factors), some of which may be modifiable.
Deoxyribonucleic acid (DNA) aberrations, critical for tumor formation, are acquired during the initial stages, and identifying biological molecules that could restrain the excessive, uncontrolled outgrowth of tumor cells, could contribute to reducing cancer-associated morbidity and mortality.
Improving our understanding of the pathways of carcinogenesis could aid in identifying high-risk individuals and reveal probable molecular targets for cancer prevention.
About the review
In the present review, researchers elucidated non-mutagenic, reversible pathways by which risk factors promote tumor growth that can be targeted to develop cancer prevention strategies.
Multi-level carcinogenesis and tumor promotion by risk factors
During homeostasis, cellular and structural microenvironmental components surround the tissue epithelium. A tumor initiates by the gain of genetic alterations, usually oncogenic driver mutations, from exogenous or endogenous sources that injure DNA.
Subsequently, the initiated epithelial cells are subjected to environmental selection pressure and fight with neighboring cells for resources and space to sustain in the tissues. They are also eliminated (through repair, extrusion, or apoptosis).
The initiated cells are removed from tissues through non-autonomous cellular pathways (out of competition), persist non-functionally, or proliferate after gaining a selection advantage.
Risk factors may alter tissue fitness to enable the expansion of initiated cells (inflammatory processes and the generation of progeny), affecting tissues before the acquisition of oncogenic alterations.
The 'oncogenic switch,' or molecular pathways converting pre-invasive lesional tissues to invasive tumors, involves pre-invasive growths distorting tissue architecture and breaking tissue confines to form irreversible invasive tumors.
The switch may involve chromosomal instabilities (CIN), resulting in copy-number alterations (CNA) and microenvironment remodeling.
The hallmarks of tumor promotion include enhanced cell lineage susceptibility, progeny generation, cooperating inflammation, immune evasion and escape from 3D constraints, tissue takeover, and genetic alterations.
Air pollutants and smoke (including passive smoking) may cause cancers of the lung, bronchus, and trachea via interleukin (IL)-1β release from macrophages, inflammation, adaptive immunological response impairments, and aberrant extracellular matrix (ECM) thickening.
Mesothelioma may result from excessive asbestos exposure via IL-1β release through the NLR family pyrin domain containing 3 (NLRP3) inflammasomes. Cancer types associated with tobacco smoking include the gastrointestinal tract, liver, lung, renal, urinary system, and acute-type myeloid leukemia.
Underlying mechanisms include IkappaB Kinase (IKKb)/nuclear factor kappa B (NF-kB)-mediated cytokine production in pulmonary myeloid cells, enhanced oncogenic mitogen-activated protein kinase (MAPK) signaling, and intestinal microbial dysbiosis.
Obesity and poor nutrition promote tumor formation by cyclooxygenase-2 (COX-2)-mediated KRAS activation and pancreatic inflammation, reducing oncogenic cell extrusion, altering the ECM, and lowering T lymphocyte competency, which enhances progeny generation.
Excessive alcohol intake could increase cancer risk by altering estrogen and serological insulin-like growth factor (IGF) levels, reducing cytotoxic T lymphocyte counts, and increasing macrophage counts.
Ultraviolet radiation may promote the formation of skin melanoma by inducing oncogenic melanocyte proliferation and impairing adaptive immune responses.
Human papillomavirus (HPV) infection could increase the risk of cervical and maxillofacial cancers due to increased inflammation. Helicobacter pylori infections can promote gastric cancer through altered β-cadherin/E-catenin level-mediated differentiation.
Epstein-Barr virus (EBV) infections promote lymphoma, nasopharyngeal tumors, and gastric tumors due to aberrant methylation, and Hepatitis B and C infections potentiate hepatic cancers due to increased cellular inflammation and tissue fibrosis.
Approaches to prevent cancer
The tumor promotion mechanisms could be targeted to prevent cancer. The cancer-preventive strategies depend on the interventions' therapeutic indices and the risk-benefit ratio for application in high-risk individuals or at the population level.
Smoking cessation could halt the assimilation of genomic alterations and lower tissue inflammation and cellular proliferation, allowing gradual tissue recolonization by cells with low mutational burdens.
Lifestyle changes, such as diet improvements, especially for obese individuals, can reduce the risk of endometrial, colorectal, and breast cancers.
Tamoxifen (selective estrogen receptor modulator) hormone therapy lowers breast cancer risk by reducing susceptible tumor-initiating cell counts and decreasing the proliferation rate.
Anti-IL-1β therapies could aid in preventing lung cancer by reducing tumor-associated inflammation. Cancer vaccines (HPV vaccines for cervical cancer, Hepatitis B for liver cancers) promote immunological surveillance for neoantigens related to particular cancers or pharmacological modulators of healthy tissue fitness for driving mutant cell elimination.
Mucin-1 and epidermal growth factor receptor (EGFR) vaccines prevent immune evasion by tumor cells. Antibiotics used to manage H. pylori infections may prevent gastric cancer. Non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin usage could prevent esophageal and colorectal cancer in susceptible individuals.
Healthy tissue fitness modulators such as notch transcription factor inhibitor 1 (NOTCH1) and Notum inhibitors act at the tissue takeover mechanism, whereas epigenetic targets such as bromodomain-containing protein 4 (BRD4) inhibitors target susceptible cell lineages. ECM modulators, including lysyl oxidase 2 (LOXL2) inhibitors, target the 3D constraints of tumor escape.
Based on the review findings, cancer risk factors may promote tumor formation via multiple non-mutagenic mechanisms that can be targeted to develop strategies to prevent cancer.
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