PROCESSES, PATHWAYS, AND MECHANISMS

Self-sufficiency in growth signals

What is the hallmark of cancer most often driven by the activation of oncogenes or mutations in proto-oncogenes?

Evading growth suppressors

What hallmark of cancer is often facilitated by the inactivation of tumor-suppressor genes?

Deregulating cellular metabolism (Altered cellular metabolism)

What hallmark involves tumors switching to aerobic glycolysis?

Evasion of apoptosis (Resisting cell death)

What hallmark involves resistance to programmed cell death?

Limitless replicative potential (Enabling replicative immortality)

What hallmark allows tumors to avoid cellular senescence and mitotic catastrophe?

Sustained angiogenesis (Inducing angiogenesis)

What hallmark requires tumors to make blood vessels to create pathways for nutrient supply?

Activating invasion and metastasis (Ability to invade and metastasize)

What hallmark involves the tumor cells spreading and establishing metastatic lesions?

Evasion of Immune Surveillance (Avoiding immune destruction)

What hallmark involves the tumor evading recognition and destruction by the host immune response?

Genomic Instability (Genome instability & mutation)

What enabling characteristic accelerates the acquisition of genetic and epigenetic alterations necessary for the hallmarks?

Tumor-promoting inflammation (Cancer-enabling inflammation)

What enabling characteristic involves an inflammatory reaction that promotes changes conferring the hallmarks of cancer?

Carcinogenesis

What is the process that is described as multifactorial and involving viruses as initiators of tumor formation?

Viral transformation

What process is studied using whole animal studies and cultured cells to determine how viral genetic material alters normal cells?

DNA virus mechanism (Disruption of cellular tumor suppressor genes)

What mechanism of oncogenesis involves producing proteins that disrupt host cell growth via cellular tumor suppressor genes?

RNA virus mechanism (Involvement in cellular oncogenes)

What mechanism of oncogenesis involves influencing cellular oncogenes, pushing proto-oncogenes to become oncogenes?

Highly oncogenic transformation

What mechanism allows RNA viruses to directly transform the host cell by having oncogenes at the cellular level?

Weakly oncogenic transformation (Slow transformers)

What mechanism do RNA viruses use to alter the host mechanism indirectly, making it conducive to carcinogenesis, typically seen in human viruses?

Promoter Insertion Sequence

What RNA virus mechanism involves inserting a sequence before the proto-oncogenic sequence, activating it to become oncogenic?

DNA virus complex formation

What specific mechanism involves DNA viruses forming complexes with tumor suppressor genes, leading to the loss of "brakes" and continuous cell division?

G1 Checkpoint bypass

What molecular mechanism is stopped when DNA viruses form a complex with pRB, causing the cell to go straight towards the synthesis phase?

Polyomavirus Early Phase Transcription

What phase of polyomavirus transcription happens after cell infection and produces large T and small t antigens needed for transformation?

Polyomavirus Late Phase Transcription

What phase of polyomavirus transcription happens after a few days and produces envelope proteins and viral coat for assembly?

Viral persistence

What EBV hallmark of latency means the virus continues to survive within the host?

Restricted expression

What EBV hallmark of latency means only antigens are expressed, but not capsid proteins and glycoproteins?

Potential for reactivation

What EBV hallmark of latency means the virus, hiding in the germinal center, may subsequently re-enter the lytic cycle?

Adsorption and Penetration (EBV)

What is the first step of the EBV lytic phase where the viral envelope glycoprotein gp350 interacts with the CD21 receptor on the B cell?

Episome formation

What occurs inside the B cell nucleus during EBV replication, where the virus creates a genetic element outside the host chromosome?

B cell immortalization

What process is facilitated by EBV antigens (LMP 1, EBNA 2, and EBER 3) inside the nucleus, allowing B cells to remain alive until the host's life cycle?

Virus Reactivation (EBV)

What occurs when B cells go out of germinal centers, allowing the lytic cycle and potentially oncogenesis?

Latent phase (Herpesviridae)

What unique life cycle stage of Herpesviridae involves no viral replication, where the virus hides inside the host?

Lytic phase (Herpesviridae)

What unique life cycle stage of Herpesviridae involves active viral replication?

HBV Replication

What process occurs in both the nucleus and cytoplasm of the host cell for the Hepatitis B virus?

HBV cccDNA formation

What state does HBV DNA become in the nucleus before transcription into proteins and RNA?

HBV encapsidation

What process occurs when mRNA leaves the nucleus of an HBV-infected cell, during which HBcAg is assembled from the capsid?

Reverse transcription (HBV)

What process starts with DNA synthesis once RNA is translated during HBV replication?

RNA virus direct translation

What positive-sense single-stranded RNA (+ssRNA) replication process uses the host ribosomes to produce viral protein?

RNA-dependent RNA polymerase (RdRp) activity

What enzyme copies +ssRNA and creates -ssRNA, which is then used as a template to synthesize more +ssRNA in non-retroviral RNA replication?

Retroviral +ssRNA replication strategy

What process requires retroviral RNA to be converted first to DNA using reverse transcriptase?

Reverse transcription (Retroviral)

What process converts retroviral +ssRNA to negative-sense single-stranded DNA (-ssDNA) using RNA-dependent DNA polymerase (RdDp)?

dsDNA synthesis (Retroviral)

What process uses DNA-dependent DNA polymerase (DdDp) to make a complimentary copy of the -ssDNA?

Provirus integration

What occurs when dsDNA from the HTLV-1 virus is incorporated into the host chromosome?

T cell proliferation dependence

What mechanism ensures HTLV-1 viral replication continues at low numbers, as it is dependent on the host cell growth?

Nonlethal Genetic Damage

What lies at the heart of carcinogenesis?

Tumor clonal expansion

What process forms a tumor by the expansion of a single precursor cell that has incurred genetic damage?

Gain of function mutations

What type of mutation results from proto-oncogene mutations, allowing them to transform cells despite the presence of a normal copy of the gene?

Loss-of-function mutations

What type of mutation results from tumor suppressor gene mutations, requiring both alleles to be damaged before transformation can occur?

Enhanced survival

What is the consequence of apoptosis-regulating gene mutations due to less cell death?

Mutator phenotype

What state is acquired by cells with loss-of-function mutations affecting DNA repair genes, leading to genomic instability and accelerated mutation rate?

Stepwise accumulation of genetic alterations

What is the manner in which progression from adenoma to invasive malignancy occurs in colon carcinoma development?

ER-positive (luminal) pathway

What is the molecular path of breast carcinoma development that begins with flat epithelial atypia and is often driven by PIK3CA mutations?

HER2-positive route

What is the ER-negative pathway of breast carcinoma driven by HER2 amplification?

Triple-negative (basal-like) route

What is the ER-negative pathway of breast carcinoma associated with BRCA1 and TP53 mutations?

Physiologic growth factor-induced signaling pathway

What pathway involves a growth factor binding to a receptor, activating downstream pathways, and ultimately leading to transcription factors enabling cell entry and progression into the cell cycle?

Autocrine loop creation

What mechanism allows some cancers to synthesize the same growth factor they are responsive to, promoting sustained proliferation?

Constitutively active oncoproteins

What drives cell proliferation in cancer when aberrations occur in multiple growth factor signaling pathways?

Loss of intrinsic GTPase activity

What is the consequence of point mutations in RAS genes, leading to elevated cell proliferation?

G1/S cell cycle checkpoint disruption

What is the most important cell cycle checkpoint in cancer, as its impairment drives uncontrolled growth, impairs DNA repair, and creates a mutator phenotype?

Two-Hit Hypothesis (Knudson's)

What hypothesis explains that two mutations involving both alleles of a tumor suppressor gene, like RB, are required to produce retinoblastoma?

RB inactivation by hyperphosphorylation

What state shifts the RB protein from active to inactive when passing through the G1/S cell cycle transition, often dysregulated in cancer?

RB inactivation by loss-of-function

What molecular mechanism causes uncontrolled progression in the cell cycle when RB cannot function anymore?

WNT pathway regulation

What signaling pathway in colonic epithelium is negatively regulated by the APC tumor suppressor gene?

β-catenin degradation

What normal process is promoted by APC in the absence of WNT growth factors to prevent accumulation of this transcription factor?

Metabolic reprogramming

What is enabled by mutations in oncogenes and tumor suppressor genes, allowing tumors to adopt growth-promoting metabolic alterations?

Aerobic glycolysis (Warburg Effect)

What metabolic process is characterized by high glucose uptake and increased conversion of glucose to lactose (fermentation) instead of oxidative phosphorylation?

Autophagy

What metabolic alteration involves cells cannibalizing their own organelles, proteins, and membranes as carbon sources during severe nutrient deficiency?

Oncometabolism

What metabolic alteration involves mutation in a Krebs cycle enzyme (IDH) producing oncometabolites that alter the epigenome?

Intrinsic (mitochondrial) pathway incapacitation

What pathway's lesions are most commonly involved in cancer, leading to resistance to apoptosis?

Evasion of senescence

What process is circumvented by the disruption of the G1/S cell cycle checkpoint, enabling limitless replicative potential?

Evasion of mitotic crisis

What is achieved by the reactivation of telomerase, which lengthens telomeres and enables tumors to avoid cell death due to shortening telomeres?

Breakage-fusion-bridge cycle

What repair cycle occurs in cells with mutated TP53 that attempt to repair DNA damage, often leading to the acquisition of more mutations?

Neovascularization

What is the process essential for tumor growth, nutrient supply, and propagation, which facilitates tumor access to vessels for metastasis?

HIF1α stabilization

What mechanism occurs under hypoxia to promote the production of VEGF and bFGF?

Epithelial-mesenchymal transition (EMT)

What process promotes a pro-migratory phenotype in tumor cells by downregulating epithelial markers (E-cadherin) and upregulating mesenchymal markers?

Degradation of ECM

What step in the metastatic cascade is achieved by the overexpression of proteases like matrix metalloproteinases (MMPs) and cathepsin D?

Attachment to novel ECM components

What step in the metastatic cascade involves tumor cells binding to the modified matrix to promote invasion, making them resistant to anoikis?

Migration and Invasion

What final step of invasion involves tumors moving through the degraded ECM into the vascular space, facilitated by actin cytoskeleton contraction?

Anoikis resistance

What characteristic do free tumor cells exhibit once the ECM is degraded, allowing them to survive after losing intercellular junctions?

Vascular dissemination, homing, and colonization

What stage of the metastatic cascade follows invasion of the ECM, where the tumor travels via the blood vessels to distant tissues?

Seed and soil hypothesis

What concept suggests that tumor cells have tropism for specific distant tissues that provide a fertile environment for them to colonize?

Multicellular aggregates migration

What form are circulating cells more likely to migrate in when establishing metastases?

Fibrin deposition promotion

What mechanism involving polyphosphate activation of Factor XII (contact factor) stabilizes tumor cell groups/emboli in circulation?

CD8+ cytotoxic T-cell (CTL) responses

What is the principal immune mechanism mediated by the immune system for tumor eradication?

Loss or reduced expression of MHC molecules

What is one mechanism of immune evasion used by cancers to avoid T cell recognition?

Inhibition of T cell activation via “Checkpoints”

What mechanism of immune evasion involves tumors actively upregulating negative regulatory pathways like CTLA-4 and PD-1?

Immune checkpoint blockade

What therapeutic approach uses agents that block CTLA-4, PD-L1, and PD-1 to lift the inhibition of cell-mediated regulation and allow the immune system to handle the tumor?

DNA mismatch repair (DMMR)

What DNA repair system works as "spell checkers" during DNA replication?

Microsatellite instability

What occurs when defects in DNA mismatch repair lead to increased or decreased lengths of tandem nucleotide repeats throughout the genome?

Nucleotide excision repair (NER)

What DNA repair mechanism fixes cross-linking of pyrimidine residues (pyrimidine dimers) induced by UV radiation?

Homologous recombination repair

What DNA repair mechanism fixes covalent DNA cross-links and double-stranded DNA breaks?

Proofreading (DNA Polymerase)

What inherent enzymatic activity of DNA polymerase, when mutated, leads to highly mutated cancers like endometrial and colon carcinomas?

Somatic gene rearrangements

What process in T and B cells, including V(D)J recombination and class switch recombination, is error-prone and associated with lymphoid neoplasms?

Chromosomal Translocations

What is the most common chromosomal rearrangement that activates proto-oncogenes, resulting in overexpression or the formation of a fusion gene?

Promoter or enhancer substitutions

What translocation mechanism results in the overexpression of a proto-oncogene?

Fusion gene formation

What translocation mechanism transcribes a novel oncogenic protein (e.g., BCR-ABL)?

Differentiation Therapy

What type of treatment for Acute Promylelocytic Leukemia (APML) involves ATRA binding to PML-RARA to displace repressor complexes, allowing malignant promyelocytes to mature into neutrophils?

Silencing of tumor suppressor genes

What epigenetic change occurs via local hypermethylation of DNA?

Initiation (Chemical Carcinogenesis)

What step in chemical carcinogenesis involves the exposure of cells to a sufficient dose of a carcinogenic agent, causing permanent DNA damage (mutations)?

Promotion (Chemical Carcinogenesis)

What step in chemical carcinogenesis involves the subsequent proliferation (multiplication) of initiated (mutated) cells?

Metabolic conversion

What process do indirect-acting carcinogens require to become active carcinogens, often performed by cytochrome P-450 enzymes?

Ionizing radiation mechanism

What mechanism of DNA damage involves electromagnetic and particulate radiations causing chromosomal breakage, translocations, and point mutations?

UVB radiation mechanism

What mechanism of DNA damage involves inducing pyrimidine dimers (cross-linking of adjacent thymidine residues) within DNA?