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Cancer cell

A cancer cell is an abnormal cell that proliferates uncontrollably, disregards normal regulatory signals, and can invade surrounding tissues or metastasize to distant sites in the body, forming the basis of malignant tumors.^[1] Unlike normal cells, which divide in a controlled manner to maintain tissue function and repair, cancer cells acquire mutations that disrupt this balance, leading to their hallmark behaviors of sustained growth, evasion of cell death, and potential for widespread dissemination.^[2] The defining characteristics of cancer cells stem from genetic and epigenetic alterations that enable them to bypass the checkpoints governing normal cellular behavior.^[3] For instance, they often exhibit self-sufficiency in growth signals by producing their own stimulatory factors or overexpressing receptors, allowing proliferation without external cues.^[4] They also show insensitivity to antigrowth signals, ignoring inhibitors like tumor suppressor proteins such as p53 or Rb, which normally halt division in response to damage or overcrowding.^[4] Additionally, cancer cells resist programmed cell death (apoptosis) through mechanisms like upregulation of anti-apoptotic proteins (e.g., Bcl-2 family members), enabling survival under stressful conditions that would eliminate normal cells.^[3] Beyond these core traits, cancer cells demonstrate unlimited replicative potential by maintaining telomere length via telomerase activation, avoiding the senescence that limits normal cell divisions to roughly 50-70 cycles (the Hayflick limit).^[4] They further promote angiogenesis to secure nutrient supply by secreting factors like vascular endothelial growth factor (VEGF), and acquire capabilities for tissue invasion and metastasis, often through epithelial-to-mesenchymal transition (EMT) that enhances motility and extracellular matrix degradation.^[3] These acquired abilities, collectively termed the "hallmarks of cancer," evolve through multistep accumulation of mutations in oncogenes and tumor suppressor genes, driven by factors such as environmental carcinogens, inherited predispositions, or chronic inflammation.^[5] In the context of disease, cancer cells originate from any tissue type but share these dysfunctional traits, classifying malignancies by their cell of origin (e.g., carcinomas from epithelial cells, sarcomas from mesenchymal cells).^[6] Their uncontrolled expansion disrupts organ function and, if untreated, can lead to systemic effects like cachexia or organ failure, underscoring the need for therapies targeting these specific vulnerabilities, such as checkpoint inhibitors or targeted molecular agents.^[1]

Definition and Characteristics

Hallmarks of Cancer

The hallmarks of cancer delineate the essential functional capabilities that enable normal cells to undergo malignant transformation, acquiring traits that sustain uncontrolled proliferation and survival in diverse tissue environments. Originally proposed in 2000, these hallmarks provide a conceptual framework for understanding the multistep evolution of tumors, emphasizing how cancer cells subvert normal regulatory circuits to promote their own growth and dissemination.^[7] This framework has since been refined to include enabling characteristics that facilitate hallmark acquisition and emerging hallmarks reflecting additional adaptive strategies observed in advanced cancers.00127-9) In 2022, the framework was further updated to incorporate new dimensions, including unlocking phenotypic plasticity as a new hallmark capability, nonmutational epigenetic reprogramming and polymorphic microbiomes as additional enabling characteristics, and the influence of senescent cells in the tumor microenvironment.^[5] Collectively, these traits distinguish malignant cells from their normal counterparts by conferring selective advantages that drive tumor progression, such as sustained proliferation through oncogene activation or resistance to programmed death signals. The six original hallmarks represent the foundational biological capabilities acquired during tumorigenesis. Self-sufficiency in growth signals allows cancer cells to proliferate independently of exogenous mitogenic stimuli, often through autocrine loops where cells produce their own growth factors like platelet-derived growth factor (PDGF) in glioblastomas or overexpression of receptors such as HER2 in breast cancer, bypassing the need for stromal-derived signals.^[7] Insensitivity to antigrowth signals enables evasion of tumor suppressor pathways, for instance via disruption of the retinoblastoma (pRb) pathway through mutations in TGF-β receptors or loss of pRb function, as seen in human papillomavirus (HPV)-associated cervical cancers where the viral E7 protein inactivates pRb.^[7] Evasion of apoptosis confers resistance to programmed cell death, a critical barrier to tumor expansion, achieved through inactivation of p53 (altered in over 50% of cancers) or overexpression of anti-apoptotic proteins like Bcl-2, which inhibits mitochondrial outer membrane permeabilization.^[7] Limitless replicative potential overcomes the Hayflick limit of normal cell division by reactivating telomerase in 85-90% of tumors, maintaining telomere length to prevent replicative senescence, or via alternative lengthening of telomeres (ALT) mechanisms in some sarcomas.^[7] Sustained angiogenesis ensures nutrient and oxygen supply for expanding tumors beyond the diffusion limit of 100-200 μm, primarily through upregulation of vascular endothelial growth factor (VEGF) and fibroblast growth factors (FGFs), often triggered by hypoxia-inducible factors or p53 loss.^[7] Tissue invasion and metastasis, responsible for approximately 90% of cancer mortality, involves alterations in cell adhesion (e.g., downregulation of E-cadherin) and extracellular matrix remodeling via proteases like matrix metalloproteinases (MMPs), enabling local invasion and distant colonization.^[7] Two enabling characteristics underpin the acquisition and maintenance of these hallmarks by fostering an environment conducive to genetic and epigenetic changes. Genome instability accelerates the mutation rate, generating the diverse variants needed for tumor evolution; this arises from defects in DNA repair pathways, such as mismatch repair deficiencies in hereditary nonpolyposis colorectal cancer, or centrosome amplification leading to chromosomal instability.00127-9) Tumor-promoting inflammation recruits immune cells that release cytokines and growth factors, akin to wound healing but chronically, enhancing proliferation and survival; for example, interleukin-6 (IL-6) and tumor necrosis factor (TNF) from infiltrating macrophages support oncogene-driven growth in various carcinomas.00127-9) Two emerging hallmarks highlight adaptive reprogramming in cancer cells. Reprogramming energy metabolism, often termed the Warburg effect, shifts cells toward aerobic glycolysis even in oxygen-rich environments, supporting rapid biosynthesis; this is driven by oncogenes like MYC or PI3K/AKT activation, which upregulate glucose transporters and glycolytic enzymes to fuel nucleotide and lipid synthesis for proliferation.00127-9) Evading immune destruction allows tumors to dodge recognition and elimination by the adaptive and innate immune systems, through mechanisms such as PD-L1 expression on cancer cells to inhibit T-cell activity via PD-1 blockade or recruitment of regulatory T cells to suppress anti-tumor responses.00127-9) The 2022 update expands the framework by recognizing unlocking phenotypic plasticity as a hallmark, enabling cells to undergo dedifferentiation, blocked differentiation, or transdifferentiation, which facilitates adaptation to therapeutic pressures and metastasis. It also introduces nonmutational epigenetic reprogramming as an enabling characteristic, where heritable changes in gene expression without DNA alterations drive tumor heterogeneity. Polymorphic microbiomes are highlighted as another enabler, with microbial communities influencing inflammation, metabolism, and immune evasion in the tumor microenvironment. Additionally, senescent cells—from cancer cells, fibroblasts, or endothelial cells—are noted as a key component, promoting tumorigenesis through secretion of pro-inflammatory factors despite their non-proliferative state. These additions reflect evolving insights into cancer's complexity and inform novel therapeutic strategies.^[5]

Differences from Normal Cells

Cancer cells exhibit distinct morphological differences from normal cells, primarily characterized by irregular shapes, increased size variation known as anisocytosis, and enlarged nuclei that appear hyperchromatic due to increased DNA content and prominent nucleoli.^[8] These alterations arise from uncontrolled proliferation and genetic instability, contrasting with the uniform, organized morphology of normal cells that maintain structural integrity within tissues.^[9] For instance, normal cells typically display consistent nuclear-to-cytoplasmic ratios and symmetrical contours, while cancer cells often have scarce cytoplasm and pleomorphic features that disrupt tissue architecture.^[8] In terms of behavior, cancer cells lose contact inhibition, allowing them to proliferate beyond the monolayer formation seen in normal cells, and gain anchorage independence, enabling growth without attachment to a substrate or extracellular matrix.^[10] This anchorage independence facilitates survival in low-adhesion environments, such as during metastasis, unlike normal cells that require adhesion for proliferation and undergo anoikis—a form of programmed cell death—upon detachment.^[11] Consequently, cancer cells can form disorganized masses, invading surrounding tissues, in stark contrast to the orderly layers formed by normal epithelial cells that respect boundary signals.^[12]^[13] Regulatory differences further distinguish cancer cells, including disrupted cell cycle checkpoints that permit unchecked division despite DNA damage, reduced differentiation leading to immature phenotypes, and high intratumoral heterogeneity where subpopulations vary in growth rates and responses to stimuli.^[14] Normal cells adhere to stringent checkpoints, such as those at G1/S and G2/M phases, ensuring fidelity in replication and differentiation into specialized functions, whereas cancer cells bypass these via mutations in regulators like p53 or cyclins.^[14] This heterogeneity, driven by non-genetic factors like epigenetic variations, allows cancer cell populations to adapt dynamically, evading therapies that target uniform traits in normal cells.^[15] These regulatory shifts align with broader hallmarks, such as sustained proliferative signaling, but manifest as observable deviations in cell behavior and organization.^[14]

Classification

By Tissue Origin

Cancer cells are classified by the tissue or cell type from which they originate, a system that provides a foundational histological framework for diagnosis and treatment. This histological classification distinguishes tumors based on their embryonic or adult tissue lineage, such as epithelial, mesenchymal, or hematopoietic origins, and has evolved through standardized international systems to ensure consistency in pathology.^[6] The World Health Organization (WHO) Classification of Tumours, initiated by a 1956 resolution of the WHO Executive Board, represents the authoritative standard, with its first edition published in the 1960s and subsequent updates incorporating advances in microscopy and pathology to refine tissue-based categorizations.^[16] The predominant category is carcinomas, which arise from epithelial tissues lining organs and glands, accounting for 80-90% of all human cancers due to the widespread distribution of epithelial cells throughout the body.^[6] Within carcinomas, malignant transformations often progress from benign precursors, such as adenomas (benign glandular tumors) to adenocarcinomas (malignant glandular cancers), the latter characterized by invasive growth and potential for distant spread; common examples include lung adenocarcinoma and colorectal adenocarcinoma.^[17] Squamous cell carcinomas, another major subtype, originate from squamous epithelium in areas like the skin, lungs, and cervix, frequently developing from premalignant lesions like actinic keratosis.^[6] Sarcomas derive from mesenchymal tissues, including connective, supportive, or soft tissues such as bone, cartilage, muscle, and fat, and represent a rarer malignancy comprising about 1% of adult cancers but more common in children and young adults.^[6] Benign counterparts, like osteomas (benign bone tumors), contrast with malignant forms such as osteosarcoma, which exhibits aggressive bone destruction and a higher incidence in adolescents.^[18] Other sarcomas include leiomyosarcoma from smooth muscle and liposarcoma from adipose tissue, highlighting the diverse mesenchymal origins and the malignant shift involving loss of tissue-specific differentiation.^[6] Leukemias and lymphomas originate from hematopoietic and lymphoid tissues, respectively, and are classified separately from solid tumors due to their liquid or systemic nature. Leukemias involve malignant proliferation of immature blood-forming cells in the bone marrow, leading to overproduction of abnormal white blood cells, with subtypes including acute myeloid leukemia and chronic lymphocytic leukemia; these differ from benign hematologic disorders by their uncontrolled clonal expansion.^[6] Lymphomas, solid malignancies of lymphocytes, include Hodgkin lymphoma (characterized by Reed-Sternberg cells) and non-Hodgkin lymphoma, often arising in lymph nodes or extranodal sites like the gastrointestinal tract, where malignant transformation disrupts normal immune function.^[19] Other categories encompass germ cell tumors, which develop from primordial germ cells in the gonads or extragonadal sites like the mediastinum, and can be benign (e.g., mature teratomas) or malignant (e.g., seminomas or yolk sac tumors), with the latter showing pluripotential differentiation mimicking embryonic tissues.^[20] Mixed tumors, such as carcinosarcomas combining epithelial and mesenchymal elements, further illustrate the histological diversity within tissue origins, though molecular subtyping refines these groupings for precision oncology.^[6]

By Molecular Subtypes

Cancer cells are increasingly classified by molecular subtypes, which delineate distinct genetic, proteomic, and transcriptomic profiles that refine categorization beyond tissue origin and morphology. This approach evolved from early 20th-century histological systems to modern genomic paradigms, driven by initiatives like The Cancer Genome Atlas (TCGA), which sequenced over 11,000 primary tumors to reveal subtype-specific alterations across cancers.^[21] The transition emphasizes multi-omics integration, combining DNA sequencing, RNA expression, and protein data to capture tumor heterogeneity and improve prognostic accuracy over purely morphological methods.^[22] Recent editions of the WHO Classification of Tumours (5th edition, 2020-2025) further incorporate molecular features into histological categories for enhanced precision. Key techniques for molecular subtyping include next-generation genomic sequencing to identify driver mutations, immunohistochemistry (IHC) to assess protein biomarkers, and gene expression profiling to cluster tumors based on transcriptomic signatures. For instance, the PAM50 assay uses quantitative reverse transcription PCR on 50 genes to classify breast cancer into luminal A, luminal B, HER2-enriched, basal-like, and normal-like subtypes, with luminal A tumors showing the highest proliferation stability.^[23] IHC is pivotal for detecting HER2 overexpression in breast cancer cells, where membrane staining intensity scores guide subtype assignment, while whole-exome sequencing uncovers somatic variants like BRAF V600E in melanoma cells, present in approximately 50% of cutaneous melanomas.^[24] In lung adenocarcinoma, KRAS mutations—often G12C or G12D—define a major subtype, frequently co-occurring with STK11/LKB1 alterations in 15-25% of KRAS-mutant cases, as identified through integrative genomic analyses.^[25] These molecular subtypes carry significant prognostic implications, influencing survival outcomes and therapeutic decision-making in precision oncology as of the early 2020s. For example, early-stage HER2-positive breast cancer has a 5-year overall survival rate exceeding 90% with targeted therapies like trastuzumab, while luminal A subtypes exceed 95%.^[26] BRAF-mutated melanoma subtypes show variable prognosis, with V600E variants linked to younger onset but poorer response to standard therapies compared to wild-type tumors.^[24] For metastatic KRAS-driven lung adenocarcinoma, median overall survival is approximately 12 months, with co-mutations like STK11 associated with immunotherapy resistance and worse outcomes.^[27] Emerging multi-omics frameworks, such as those using machine learning on TCGA datasets, further refine these subtypes by incorporating epigenomic and proteomic layers, enabling predictions of tumor evolution and personalized risk assessment.^[28]

Microscopic Features

Nuclear Alterations

Cancer cells exhibit distinct nuclear alterations that contribute to their identification under microscopy and reflect underlying genomic instability. One prominent feature is nuclear enlargement, often accompanied by anisonucleosis—a variation in nuclear size—and pleomorphism, characterized by irregular nuclear shapes. These changes arise primarily from increased DNA content due to polyploidy or aneuploidy, which disrupts normal nuclear architecture.^[29]^[30] Hyperchromasia, or intensified nuclear staining, further accentuates these alterations, resulting from condensed chromatin and elevated nucleic acid density that enhances basophilic appearance during histological examination.^[31]^[32] Prominent nucleoli are another hallmark of cancer cell nuclei, appearing enlarged and multiple in number compared to normal cells. This prominence stems from heightened ribosomal RNA (rRNA) synthesis within the nucleolus, supporting accelerated ribosome biogenesis to meet the demands of rapid protein production in proliferating tumor cells.^[33]^[34] Such nucleolar hypertrophy correlates with upregulated transcription of rRNA genes, a process essential for the metabolic reprogramming observed in malignancies.^[35] Chromatin within cancer cell nuclei often displays margination, where it adheres to the nuclear periphery, and clumping into dense aggregates, deviating from the evenly dispersed pattern in healthy cells. These structural shifts indicate altered gene expression patterns, as chromatin remodeling influences accessibility to transcriptional machinery and epigenetic modifications.^[30]^[36] Margination and clumping can impair normal regulatory functions, promoting the dysregulation of oncogenes and tumor suppressors. Micronuclei formation represents a critical nuclear alteration linked to chromosomal instability in cancer cells, where whole chromosomes or fragments are excluded from the main nucleus during mitosis, forming small extranuclear bodies. This phenomenon arises from errors such as lagging chromosomes or acentric fragments, serving as a marker of genomic instability that drives tumor evolution.^[37]^[38] The micronucleus assay quantifies these structures by scoring their frequency in interphase cells, providing a standardized method to assess genotoxicity and chromosomal aberrations in cancer diagnostics and research.^[39]^[40]

Cytoplasmic and Structural Changes

Cancer cells often exhibit increased cytoplasmic basophilia, a bluish staining of the cytoplasm observed under light microscopy, primarily due to elevated levels of ribosomal and messenger RNA associated with heightened protein synthesis demands.^[8] This basophilia reflects the accumulation of free ribosomes and polysomes in the cytoplasm, which supports the rapid proliferation and metabolic activity characteristic of malignancy.^[8] In histological sections of tumors such as hepatocellular carcinoma, this feature manifests as intensified cytoplasmic staining alongside reduced cell volume.^[41] The cytoplasm of cancer cells frequently shows an abundance of mitochondria, adapted to fulfill the elevated bioenergetic and biosynthetic requirements despite reliance on aerobic glycolysis.^[42] These organelles increase in number through enhanced biogenesis pathways, enabling the production of intermediates for macromolecule synthesis and reactive oxygen species signaling that promote tumor progression.^[43] For instance, in aggressive cancers like breast and lung carcinomas, mitochondrial mass expansion correlates with metastatic potential and resistance to therapy.^[44] Disruption of the cytoskeleton is a hallmark structural change in cancer cells, leading to irregular cell shapes, loss of polarity, and enhanced motility essential for invasion.^[45] Alterations in actin filaments, including disorganized polymerization and abnormal bundling mediated by actin-binding proteins, contribute to these morphological irregularities and facilitate pseudopod formation for migratory behavior.^[45] In mesenchymal-type cancer cells, such as those in pancreatic ductal adenocarcinoma, stabilized or destabilized actin networks impair normal adhesion while promoting amoeboid-like movement through extracellular matrices.^[46] Organelle abnormalities further underscore the dysfunctional architecture of cancer cell cytoplasm. The Golgi apparatus often appears enlarged or fragmented, supporting increased secretory demands for extracellular matrix remodeling and growth factor release during tumor progression.^[47] In stressed cancer cells, such as those under nutrient deprivation or chemotherapy, autophagic vacuoles—double-membrane-bound structures known as autophagosomes—accumulate to degrade damaged cytoplasmic components and maintain homeostasis.^[48] These vacuoles, formed via ATG protein-mediated processes, enable survival in hypoxic tumor microenvironments but can also contribute to therapeutic resistance in cancers like glioblastoma.^[48] Examples of severe structural derangements include binucleation or multinucleation, arising from failed cytokinesis where cells complete karyokinesis but fail to divide the cytoplasm.^[49] This results in tetraploid or polyploid cells with multiple nuclei sharing a common cytoplasm, observed in anaplastic tumors such as those driven by APC mutations or ECT2 overexpression.^[49] In ovarian and colorectal cancers, such multinucleated giant cells promote genomic instability and aneuploidy, fostering aggressive phenotypes.^[50]

Etiology

Genetic Causes

Cancer cells arise from intrinsic genetic alterations that disrupt normal cellular regulation, primarily through mutations affecting oncogenes and tumor suppressor genes. Oncogenes, derived from proto-oncogenes, promote cell growth and division when activated by gain-of-function mutations, such as point mutations or gene amplifications. For instance, mutations in the RAS family of oncogenes, occurring in approximately 30% of human cancers, lead to constitutive activation of signaling pathways that drive uncontrolled proliferation. Similarly, amplification of the MYC oncogene, a transcription factor overexpressed in over 70% of cancers, enhances cell cycle progression and metabolic reprogramming, facilitating tumorigenesis.^[51]^[52] In contrast, tumor suppressor genes inhibit cell growth, and their loss-of-function mutations or deletions allow malignant transformation. The TP53 gene, mutated in more than 50% of cancers, encodes the p53 protein, which normally induces cell cycle arrest, DNA repair, or apoptosis in response to damage; its inactivation impairs these safeguards, enabling survival of genetically unstable cells.^[53] These genetic changes can be inherited as germline mutations, conferring predisposition to hereditary cancers. For example, pathogenic variants in BRCA1 and BRCA2 genes, which repair DNA double-strand breaks, increase lifetime breast cancer risk to 55-72% for BRCA1 carriers and 45-69% for BRCA2 carriers by age 70-80, with ovarian cancer risks of 39-44% and 17-31%, respectively; these mutations account for 5-10% of breast cancers overall.^[54]^[55] Most cancer-initiating genetic alterations, however, are somatic mutations acquired during a lifetime through multistep carcinogenesis, where sequential accumulation of mutations transforms normal cells into malignant ones. In this process, driver mutations confer selective growth advantages to cells, such as enhanced proliferation or survival, while passenger mutations arise incidentally without functional impact but hitchhike with drivers during clonal expansion; genome sequencing reveals tumors often harbor 2-8 driver mutations alongside thousands of passengers.^[56]^[57] Chromosomal abnormalities further contribute to cancer development by altering gene dosage or creating fusion genes. Aneuploidy, an imbalance in chromosome number affecting nearly all solid tumors, disrupts proteostasis and promotes genomic instability, acting as both a cause and consequence of malignancy. Balanced translocations, such as the t(9;22) Philadelphia chromosome in chronic myeloid leukemia (CML), fuse BCR and ABL1 genes to produce a hyperactive tyrosine kinase that drives leukemogenesis in over 95% of CML cases.^[58]^[59]

Environmental and Lifestyle Factors

Environmental and lifestyle factors play a significant role in the initiation of cancer by inducing DNA damage that can lead to oncogenic mutations in cells. These extrinsic influences interact with cellular processes, often requiring chronic exposure to accumulate sufficient genetic alterations for malignant transformation. While individual genetic susceptibilities can modulate risk, the primary impact stems from exposure to specific agents that directly or indirectly promote carcinogenesis. Chemical carcinogens, such as those in tobacco smoke, are among the most well-established environmental contributors to cancer development. Tobacco smoke contains polycyclic aromatic hydrocarbons (PAHs) like benzopyrene, which form DNA adducts that, if unrepaired, lead to mutations in critical genes; epidemiological studies show a strong dose-response relationship, where the risk of lung cancer increases linearly with pack-years smoked. Similarly, asbestos fibers, particularly chrysotile and amphibole types, cause chronic inflammation and oxidative stress in mesothelial cells, resulting in malignant mesothelioma; the International Agency for Research on Cancer (IARC) classifies asbestos as a Group 1 carcinogen based on consistent evidence from occupational cohorts demonstrating risk proportional to cumulative exposure duration and intensity. Physical agents, including ultraviolet (UV) radiation and ionizing radiation, exert genotoxic effects by directly damaging DNA structure. UV radiation, primarily UVB wavelengths from sunlight, induces cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts between adjacent thymine or cytosine bases, impairing replication and transcription; this is a key mechanism in skin cancers like melanoma, with fair-skinned individuals showing higher incidence due to reduced melanin protection. Ionizing radiation, from sources such as radon gas or medical imaging, generates reactive oxygen species and causes double-strand breaks in DNA, leading to chromosomal aberrations; atomic bomb survivor studies have established a linear no-threshold dose-response, where even low doses elevate leukemia risk. Biological agents, notably oncogenic viruses, contribute to cancer by hijacking host cellular machinery to promote uncontrolled growth. Human papillomavirus (HPV), particularly high-risk types 16 and 18, encodes E6 and E7 oncoproteins that bind and degrade p53 and Rb tumor suppressors, respectively, disabling cell cycle checkpoints and apoptosis; this is central to cervical cancer pathogenesis, with over 99% of cases linked to persistent HPV infection as per global surveillance data. Other viruses like hepatitis B virus (HBV) induce liver cancer through chronic inflammation and integration of viral DNA into host genomes, while Epstein-Barr virus (EBV) is associated with lymphomas via latent gene expression that activates NF-κB signaling. Lifestyle factors amplify cancer risk through modifiable behaviors that foster a pro-carcinogenic environment. Diets high in processed meats introduce N-nitroso compounds from nitrates and nitrites, which can form DNA-alkylating agents during digestion, elevating colorectal cancer risk; meta-analyses indicate a 18% increased relative risk per 50g daily intake. Alcohol consumption generates acetaldehyde, a mutagenic metabolite that forms DNA adducts, particularly in the upper aerodigestive tract, with risk rising dose-dependently—over 3 drinks per day triples esophageal cancer odds. Obesity promotes systemic inflammation via adipokine dysregulation and elevated insulin/IGF-1 levels, creating a microenvironment conducive to breast and endometrial cancers; cohort studies link a 5-unit BMI increase to a 20-50% higher risk for these sites.

Molecular Mechanisms

DNA Repair and Mutations

Defects in DNA repair mechanisms are a fundamental driver of genomic instability in cancer cells, allowing the accumulation of mutations that promote tumorigenesis. These defects impair the cell's ability to correct DNA damage from endogenous or exogenous sources, leading to a higher frequency of genetic alterations compared to normal cells. As a result, cancer cells exhibit elevated mutation rates, which fuel the selection of advantageous clones and contribute to tumor progression.^[60] The major DNA repair pathways include base excision repair (BER), which removes damaged bases such as those caused by oxidative stress; nucleotide excision repair (NER), which excises bulky lesions like UV-induced adducts; mismatch repair (MMR), which corrects replication errors and small insertions/deletions; homologous recombination (HR), which accurately repairs double-strand breaks (DSBs) using a sister chromatid template; and non-homologous end joining (NHEJ), an error-prone pathway that ligates DSB ends directly. Each pathway operates through specific proteins: for instance, BER involves PARP-1 and APE1, NER relies on XPA-XPG factors, MMR uses MLH1/MSH2 complexes, HR depends on BRCA1/2 and RAD51, and NHEJ requires Ku70/80 and DNA-PKcs. Defects in these pathways compromise repair fidelity, resulting in persistent DNA damage and chromosomal aberrations that characterize cancer genomes.^[60] Notable deficiencies include MMR defects associated with Lynch syndrome, an autosomal dominant condition caused by germline mutations in MLH1, MSH2, MSH6, or PMS2 genes, which lead to microsatellite instability (MSI)—a hypermutator phenotype marked by expansions or contractions in repetitive DNA sequences. This instability arises because unrepaired replication errors accumulate, particularly in microsatellites, driving frameshift mutations in target genes and increasing cancer risk for colorectal, endometrial, and other tumors. Similarly, HR defects in BRCA1- or BRCA2-mutated cells impair DSB repair, causing genomic scars such as loss of heterozygosity and structural variants, which predispose individuals to breast, ovarian, and prostate cancers by allowing unrepaired breaks to propagate lethal or oncogenic changes.^[61]^[62] Mutation rates in cancer cells are substantially elevated due to these repair deficiencies; while normal somatic cells maintain a rate of approximately 10^{-9} mutations per base pair per cell division, cancer cells with defects like MMR deficiency can exhibit 100- to 1,000-fold increases, reaching 10^{-6} to 10^{-7} per base pair per division in hypermutated tumors. This hypermutation, often quantified as MSI-high status, amplifies the genetic variation within the tumor.^[60]^[63] The consequences of unrepaired DNA damage include accelerated clonal evolution and intratumor heterogeneity, where subpopulations of cancer cells acquire diverse mutations that confer survival advantages, such as resistance to therapy or enhanced invasiveness. This evolutionary process, driven by repair pathway failures, enables the tumor to adapt dynamically, with dominant clones emerging from a heterogeneous pool shaped by selective pressures.30066-1)

Telomerase and Immortality

Telomeres are nucleoprotein structures at the ends of linear chromosomes, consisting of tandem repeats of the hexanucleotide sequence TTAGGG in humans, typically spanning 5–15 kilobases in length.^[64] In normal somatic cells, telomeres progressively shorten with each cell division due to the end-replication problem, where DNA polymerase cannot fully replicate the 3' ends of chromosomes, leading to a loss of 50–200 base pairs per replication cycle.^[65] This telomere attrition eventually triggers a DNA damage response, culminating in cellular senescence or apoptosis, thereby limiting the replicative lifespan of cells and serving as a tumor-suppressive mechanism.^[66] Cancer cells evade this replicative senescence by reactivating telomerase, a ribonucleoprotein enzyme that extends telomeres using an RNA template to add TTAGGG repeats to chromosome ends.^[67] Telomerase comprises two main components: the catalytic reverse transcriptase subunit encoded by the TERT gene (telomerase reverse transcriptase), which synthesizes the telomeric DNA, and the TERC RNA component (telomerase RNA component), which provides the template sequence for repeat addition.^[68] In most cancers, telomerase is upregulated through mechanisms such as TERT promoter mutations (e.g., C228T or C250T hotspots), which create binding sites for transcription factors, or TERT gene amplification, leading to sustained enzyme activity and telomere maintenance.^[69] Telomerase activity is detected in approximately 90% of human cancers, including carcinomas, but is largely absent in normal somatic tissues, where it is restricted to stem cells, germ cells, and activated lymphocytes.^[70] This high prevalence underscores telomerase's role in conferring replicative immortality, a hallmark enabling indefinite proliferation.^[71] In the remaining 10–15% of telomerase-negative cancers, telomeres are maintained via alternative lengthening of telomeres (ALT), a recombination-mediated mechanism involving break-induced replication between telomeres, often characterized by heterogeneous telomere lengths and extrachromosomal telomeric DNA.^[72] ALT relies on homologous recombination proteins and is prevalent in certain sarcomas, gliomas, and neuroendocrine tumors.^[73]

Pathological Behavior

Uncontrolled Proliferation

Uncontrolled proliferation in cancer cells arises from dysregulated cell cycle control, enabling these cells to divide rapidly and indefinitely without external signals that normally restrict growth in healthy tissues. This hallmark behavior is driven by alterations in key regulatory pathways, allowing cancer cells to bypass physiological checkpoints and maintain a proliferative state even in nutrient-poor or stressful environments. Such deregulation contrasts with normal cells, which exit the cell cycle into quiescence (G0 phase) under unfavorable conditions, highlighting how cancer cells exploit these mechanisms for survival and expansion. A primary mechanism of uncontrolled proliferation involves deregulation at the G1/S transition of the cell cycle, often due to overexpression of cyclin D and its associated kinases CDK4/6. In normal cells, cyclin D/CDK4/6 complexes phosphorylate the retinoblastoma protein (Rb), partially releasing E2F transcription factors to initiate DNA synthesis; however, in cancer, amplified cyclin D or hyperactive CDK4/6 leads to excessive Rb phosphorylation, fully derepressing E2F and driving unchecked progression into S phase.^[74] This overexpression is common in various malignancies, such as breast and lung cancers, where it sustains proliferation independent of growth factors.^[75] Cancer cells also achieve growth factor independence through autocrine signaling loops, exemplified by platelet-derived growth factor (PDGF) in gliomas. In these tumors, glioma cells produce PDGF ligands that bind and activate their own PDGF receptors (PDGFR), forming a self-stimulatory loop that activates downstream pathways like PI3K/Akt to promote continuous proliferation without paracrine support from the tumor microenvironment.^[76] Blocking this autocrine PDGF signaling inhibits Akt phosphorylation and suppresses glioma cell growth, underscoring its role in maintaining proliferative autonomy.^[76] Failures in cell cycle checkpoints further exacerbate proliferation, particularly through defects in the mitotic spindle assembly checkpoint (SAC), which normally halts mitosis until chromosomes align properly. In cancer cells, weakened SAC function—often from mutations in genes like MAD2 or BUB1—allows improper spindle attachments, leading to chromosome missegregation and aneuploidy, a state of abnormal chromosome numbers that paradoxically enhances tumorigenic potential by increasing genetic instability and adaptive proliferation.^[77] This checkpoint evasion enables cells to complete mitosis despite errors, perpetuating cycles of division. Evasion of quiescence is facilitated by reduced levels of CDK inhibitors, such as p16INK4a, which normally binds CDK4/6 to prevent Rb phosphorylation and induce G0 arrest. Alterations in the p16INK4a pathway, observed in up to 77% of bladder carcinomas, free CDK4/6 to drive proliferation by releasing other inhibitors (e.g., p27KIP1) for alternative uses and bypassing stress-induced quiescence.^[78] This deregulation not only sustains active cycling but also links to broader survival strategies, such as limited evasion of apoptosis through overlapping Rb pathway alterations.^[79]

Invasion and Metastasis

Invasion and metastasis are defining features of malignant cancer cells, enabling them to escape the primary tumor, enter circulation, and establish secondary tumors at distant sites, which accounts for over 90% of cancer-related deaths.^[80] This process begins with the acquisition of migratory and invasive capabilities, allowing cells to breach basement membranes and interstitial tissues, followed by dissemination and colonization.^[81] A pivotal mechanism in initiating invasion is the epithelial-mesenchymal transition (EMT), where cancer cells lose epithelial polarity and adhesion while gaining mesenchymal traits that promote motility.^[82] During EMT, E-cadherin expression is downregulated, disrupting cell-cell junctions, while vimentin and N-cadherin are upregulated, enhancing cytoskeletal reorganization and invasive potential.^[83] This transition is orchestrated by transcription factors such as Snail and Twist, induced by signals from the tumor microenvironment like TGF-β, and partial EMT states allow collective migration of cell clusters.^[84] To penetrate the extracellular matrix (ECM), cancer cells form specialized protrusions called invadopodia, which concentrate proteolytic activity for localized degradation.^[85] Matrix metalloproteinases (MMPs), particularly MMP-2 and MMP-9, are secreted or membrane-bound at invadopodia tips, cleaving ECM components like collagen and laminin to create paths for advancement.^[86] Invadopodia assembly involves actin polymerization driven by proteins like cortactin and Arp2/3, regulated by tyrosine kinases such as Src, enabling efficient tissue remodeling without widespread proteolysis.^[87] Intravasation occurs when invasive cells enter vascular or lymphatic systems, a rate-limiting step influenced by tumor-associated macrophages that facilitate vessel permeability.^[88] Circulating tumor cells (CTCs) must then evade anoikis, detachment-induced apoptosis, through resistance conferred by integrin-mediated signaling; for instance, β1 and β3 integrins engage ECM remnants or platelets to activate PI3K/Akt pathways, promoting survival during transit.^[89] This anoikis resistance, often amplified by EMT-induced changes, ensures a subset of CTCs remains viable despite circulatory stresses like shear forces and immune surveillance.^[81] Colonization at secondary sites requires the establishment of a supportive metastatic niche, where CTCs adapt to foreign microenvironments.^[90] Primary tumors precondition distant organs via exosomes, small extracellular vesicles carrying miRNAs and proteins that mobilize bone marrow-derived cells, induce vascular permeability, and remodel ECM to form pre-metastatic niches.^[91] For example, exosomal S100A8/A9 recruits myeloid cells to lung or liver sites, creating an inflammatory milieu that aids extravasation and outgrowth.^[92] This niche fosters dormancy escape and proliferation, transforming micrometastases into clinically detectable tumors.^[93]

Historical Development

Early Observations

The earliest documented observations of what we now recognize as cancerous growths date back to ancient civilizations, long before the advent of microscopy allowed for cellular examination. In ancient Egypt, the Edwin Smith Papyrus, dating to approximately 2500 BCE and transcribed around 1600 BCE, provides the oldest known surgical treatise describing tumors, including eight cases of breast tumors characterized as bulging masses that could not be treated surgically due to their inoperable nature.^[94] These descriptions focused on macroscopic swellings and symptoms, such as ulceration and discharge, without any reference to cellular structures, reflecting the limitations of pre-microscopic medicine. Similarly, the Ebers Papyrus from the same era mentions treatments for various tumors using ointments and incantations, underscoring an early recognition of malignant-like growths as distinct pathological entities.^[95] The development of microscopy in the 19th century marked a pivotal shift, enabling the first direct visualizations of cancer at the cellular level. In 1838, German pathologist Johannes Müller published a seminal monograph on tumors, in which he systematically analyzed microscopic sections of human neoplasms and identified distinctive "cancer cells" in breast tumors through detailed illustrations and descriptions of their granular, irregular morphology.^[96] Müller's work challenged prevailing humoral theories, such as the idea that cancer arose from lymph, by demonstrating that tumors consisted of proliferated cells rather than fluid accumulations, based on scrapings and thin slices observed under early microscopes.^[97] This observation laid the groundwork for understanding cancer as a cellular disease, though the full implications would emerge later. Building on these insights, Rudolf Virchow advanced the field in 1858 with his lectures on cellular pathology, introducing the principle "omnis cellula e cellula" (every cell from a cell), which posited that all diseases, including cancer, originate from abnormal proliferation of preexisting cells rather than spontaneous generation.^[98] Virchow's theory linked cancerous growths to dysregulated cellular division, emphasizing histological examination of tissues to identify pathological changes, such as excessive cell multiplication in organs like the liver and uterus.^[99] His approach transformed pathology from a descriptive to an explanatory science, directly influencing the study of cancer as a disorder of cellular behavior. Concurrent with these advancements, early staining techniques enhanced the visibility of cancer cells' abnormal features under the microscope. The hematoxylin-eosin (H&E) method, developed in the mid-to-late 19th century, became instrumental in highlighting pleomorphic (variably shaped) nuclei and cytoplasmic details in tumor tissues; hematoxylin, introduced for nuclear staining by Friedrich Böhmer in 1865, was combined with eosin's counterstain by around 1875 to differentiate cellular components effectively.^[100] This technique allowed pathologists to discern the irregular, hyperchromatic nuclei characteristic of cancer cells, facilitating more precise diagnoses of malignancy in biopsies.^[101]

Key Scientific Advances

In 1911, Peyton Rous demonstrated that a filterable agent from a chicken sarcoma could transmit the tumor to healthy birds, marking the first identification of an oncogenic virus and laying the groundwork for understanding viral contributions to cancer cell transformation. During the 1970s, the discovery of cellular oncogenes revolutionized cancer biology, with J. Michael Bishop and Harold E. Varmus showing that the src gene in Rous sarcoma virus originated from normal cellular DNA, which could be activated to drive uncontrolled proliferation in cancer cells; this work, building on earlier retroviral studies, earned them the 1989 Nobel Prize in Physiology or Medicine. Their 1976 findings revealed that DNA sequences related to viral oncogenes, such as src kinase, are present in normal avian and mammalian genomes, suggesting that mutations in these proto-oncogenes underlie tumorigenesis. In the 1980s and 1990s, advances in apoptosis pathways highlighted how cancer cells evade programmed cell death, exemplified by the identification of the bcl-2 gene in 1985 as a proto-oncogene involved in t(14;18) translocations in follicular lymphoma, where its overexpression inhibits apoptosis and promotes cell survival. Concurrently, the discovery of cyclins as key regulators of the cell cycle, first reported by Tim Hunt in the early 1980s through studies on sea urchin embryos showing periodic synthesis and degradation of cyclin proteins that activate cyclin-dependent kinases, provided mechanistic insights into how dysregulated proliferation arises in cancer cells; this contribution shared the 2001 Nobel Prize in Physiology or Medicine.^[102] From the 2000s onward, Douglas Hanahan and Robert A. Weinberg synthesized these insights in their seminal 2000 paper, outlining six "hallmarks of cancer" that define the acquired capabilities of cancer cells, including self-sufficiency in growth signals, insensitivity to anti-growth signals, evasion of apoptosis, limitless replicative potential, sustained angiogenesis, and tissue invasion and metastasis, which framed cancer as a disease of disrupted cellular homeostasis.^[3] Their 2011 update expanded this framework to include two emerging hallmarks—reprogramming of energy metabolism and evading immune destruction—along with enabling characteristics like genome instability and tumor-promoting inflammation, integrating genomic and systems-level views of cancer cell behavior.^[4] Parallel to these conceptual advances, CRISPR-Cas9 technology, adapted for mammalian cells in the early 2010s, enabled high-throughput functional genomics in cancer research, allowing precise knockout screens to identify essential genes and synthetic lethal interactions in tumor cells; a landmark 2014 study demonstrated genome-scale CRISPR screens in human cancer cell lines, revealing vulnerabilities like dependencies on oncogenic pathways that guide targeted therapies.^[103] These tools have since accelerated the dissection of cancer cell heterogeneity and resistance mechanisms, transforming experimental oncology.

Therapeutic Approaches

Conventional Treatments

Conventional treatments for cancer primarily include surgery, chemotherapy, and radiation therapy, which aim to eliminate or control tumors by exploiting the rapid proliferation of cancer cells while often affecting normal tissues as well. These approaches have been the cornerstone of oncology for decades, offering curative potential in many cases but limited by their non-specific nature and associated toxicities. Surgery involves the physical removal of tumor masses, providing definitive local control when feasible. Chemotherapy and radiation target cellular processes essential for division, such as DNA integrity, but can induce significant side effects due to their impact on healthy proliferating cells. Surgical excision is a primary intervention for localized tumors, where the goal is to remove the entire cancerous mass along with a margin of surrounding healthy tissue to prevent recurrence. This procedure is particularly effective for solid tumors that are accessible and have not metastasized, achieving high cure rates in early-stage cancers like melanoma or basal cell carcinoma. By directly excising the tumor, surgery addresses the pathological accumulation of cancer cells without relying on systemic agents, though it may not eradicate microscopic distant spread. Chemotherapy employs cytotoxic drugs to interfere with DNA replication and cell division in rapidly proliferating cancer cells. Alkylating agents, such as cyclophosphamide, exert their effects by forming cross-linkages between DNA strands at the guanine N-7 position via their active metabolite phosphoramide mustard, thereby preventing DNA unwinding and transcription essential for cell survival. Antimetabolites like 5-fluorouracil (5-FU) inhibit thymidylate synthase, an enzyme critical for synthesizing thymidine nucleotides needed for DNA replication, leading to nucleotide depletion and cell cycle arrest primarily in the S phase. Many chemotherapeutic agents exhibit cell cycle phase specificity, targeting cancer cells during vulnerable stages of proliferation while sparing quiescent normal cells to varying degrees. Radiation therapy utilizes ionizing radiation to induce lethal DNA double-strand breaks (DSBs) in cancer cells, a process that disrupts genomic integrity and triggers apoptosis if unrepaired. Cancer cells often display heightened radiosensitivity due to inherent deficiencies in DSB repair pathways, such as non-homologous end joining or homologous recombination, making them less able to recover from this damage compared to most normal tissues. This therapy is typically localized to the tumor site using external beam techniques, minimizing exposure to distant organs while exploiting the uncontrolled proliferation of cancer cells. A major limitation of these conventional treatments is their non-selective cytotoxicity, which affects normal rapidly dividing cells, particularly in the bone marrow, leading to myelosuppression. Myelosuppression manifests as reduced production of red blood cells, white blood cells, and platelets, increasing risks of anemia, infections, and bleeding, and often necessitates dose adjustments or supportive care like growth factors. This shared vulnerability with normal proliferative tissues underscores the need for adjunctive strategies to mitigate toxicities while enhancing antitumor efficacy.

Targeted and Emerging Therapies

Targeted therapies represent a paradigm shift in cancer treatment by selectively interfering with molecular pathways dysregulated in cancer cells, minimizing damage to healthy tissues. These approaches leverage the unique genetic and proteomic alterations in malignant cells, such as activated kinases or overexpressed receptors, to achieve precision in therapeutic intervention. Unlike conventional chemotherapy, which indiscriminately targets rapidly dividing cells, targeted therapies focus on cancer-specific vulnerabilities identified through molecular profiling.^[104] Small-molecule inhibitors are orally bioavailable compounds designed to bind and inhibit specific enzymes critical for cancer cell survival. A landmark example is imatinib, which targets the BCR-ABL fusion tyrosine kinase resulting from the Philadelphia chromosome translocation in chronic myeloid leukemia (CML) cells. By competitively binding the ATP-binding site of BCR-ABL, imatinib blocks downstream signaling pathways like PI3K/AKT and MAPK, halting uncontrolled proliferation in CML cells. In a phase 1 trial, imatinib achieved complete hematologic responses in 98% of chronic-phase CML patients and major cytogenetic responses in 31%, establishing it as the first targeted therapy to dramatically improve survival in this disease.^[105] Broader classes of tyrosine kinase inhibitors (TKIs), such as those targeting EGFR in non-small cell lung cancer or ALK in anaplastic large cell lymphoma, similarly exploit kinase addictions in cancer cells, with response rates often exceeding 70% in biomarker-selected patients.^[106] Monoclonal antibodies offer extracellular targeting by binding cell surface antigens on cancer cells, triggering immune-mediated destruction or signaling inhibition. Trastuzumab, a humanized IgG1 antibody, specifically binds the extracellular domain of the HER2 receptor overexpressed in approximately 15-20% of breast cancers, preventing HER2 dimerization and downstream activation of proliferative pathways. Additionally, trastuzumab recruits natural killer cells to induce antibody-dependent cellular cytotoxicity (ADCC), enhancing tumor cell lysis. In a pivotal phase 3 trial, adding trastuzumab to first-line chemotherapy in HER2-positive metastatic breast cancer patients doubled the median time to progression to 7.4 months compared to chemotherapy alone.^[107] Other antibodies, like rituximab targeting CD20 on B-cell lymphomas, similarly promote ADCC and complement-dependent cytotoxicity, achieving complete response rates of up to 80% in combination regimens.^[104] Emerging immunotherapies, including chimeric antigen receptor (CAR) T-cell therapies, engineer patient-derived T cells to express synthetic receptors that recognize tumor antigens. CAR-T cells targeting CD19, a surface marker on B-cell malignancies, have shown transformative efficacy in relapsed/refractory hematologic cancers. For instance, axicabtagene ciloleucel, a CD19-directed CAR-T product, reprograms T cells to release perforin and granzymes upon antigen binding, leading to targeted lysis of malignant B cells. In the ZUMA-1 trial, axicabtagene ciloleucel achieved an objective response rate of 83% in refractory large B-cell lymphoma patients, with 58% achieving complete remission at a median follow-up of 15.4 months.^[108] Telomerase inhibitors, such as imetelstat, address the immortality conferred by telomerase reactivation in cancer cells by competitively binding the telomerase RNA component, shortening telomeres and inducing senescence or apoptosis. In the phase 3 IMerge trial, imetelstat achieved 8-week red blood cell transfusion independence in 39.1% of lower-risk myelodysplastic syndrome patients refractory to erythropoiesis-stimulating agents, compared to 15% with placebo, leading to its FDA approval in June 2024.^[109]^[110] Gene therapies harness molecular tools to directly modify or destroy cancer cells. CRISPR-Cas9-based editing enables precise correction of oncogenic mutations in cancer cells, such as restoring tumor suppressor function or disrupting driver genes like KRAS. Preclinical studies have demonstrated CRISPR-mediated knockout of PD-1 in T cells to enhance anti-tumor immunity, with early-phase trials showing feasibility in editing hematopoietic stem cells for leukemia.^[111] Oncolytic viruses, engineered to selectively replicate in and lyse cancer cells with defective antiviral responses, represent another gene therapy modality. Talimogene laherparepvec (T-VEC), a modified herpes simplex virus expressing GM-CSF, infects melanoma cells, replicates intracellularly, and causes oncolysis while stimulating systemic anti-tumor immunity. In the OPTiM phase 3 trial, intratumoral T-VEC improved durable response rates to 16.3% in advanced melanoma patients versus 2.1% with GM-CSF alone, leading to its FDA approval in 2015.^[112] These approaches continue to evolve, with ongoing trials combining them for synergistic effects against heterogeneous cancer cell populations.

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Use of Chemotherapy plus a Monoclonal Antibody against HER2 for ...
Mar 15, 2001 · Trastuzumab increases the clinical benefit of first-line chemotherapy in metastatic breast cancer that overexpresses HER2.
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Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B ...
Drs. Neelapu and Locke contributed equally to this article. This article was published on December 10, 2017, at NEJM.org. Supported by Kite Pharma and the ...
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Comprehensive review of CRISPR-based gene editing
Jan 9, 2024 · The CRISPR system is a revolutionary genome editing tool that has the potential to revolutionize the field of cancer research and therapy.
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Talimogene Laherparepvec: Moving From First-In-Class to Best-In ...
Feb 21, 2022 · While T-VEC was approved for the treatment of melanoma, the virus was able to demonstrate activity against tumor cells derived from other ...Abstract · Introduction · The Development of... · Real World Experience With T...