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Malignant transformation
Stages of tumor development
Theories of cancerogenesis
Hallmarks of cancer
Oncogenes and tumor suppressors
Metastases
Interaction of tumor and organism
Cancer biomarkers
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Tumor development
Cancerogenesis
̶ The process of tumor formation is a complex involving
multiple alterations of cells/tissues and their physiologic
control mechanisms.
̶ The complexity of this process is reflected in the long
time periods required for most human cancers to
develop.
̶ Multi-step tumor progression can be depicted as a form
of Darwinian evolution occurring within tissues.
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Somatic Mutation Theory (SMT)
• Changes in the DNA of the founder cell make this cell
unable to control its proliferation.
• Clonal expansion.
Tissue Organization Field Theory (TOFT)
• Carcinogenesis is “development gone awry.”
• Normal tissue blocks the proliferation and motility of cells (tissue homeostasis).
• Disruption of the normal tissue organization leads to the loss of constraints and subsequent cell proliferation and cell invasion.
• Abnormal tissue architecture.
• Significant role of the microenvironment.
• DNA mutations are less significant.
Somatic mutations versus tissue organization
Theories of carcinogenesis
Enabling characteristics of cancer
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̶ Genomic instability and nonmutational
epigenetic reprogramming
̶ Unlocking phenotypic plasticity
̶ Tumor microenvironment
̶ Polymorphic microbiomes
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Genomic instability and non-mutational epigenetic reprogramming
Genetic alterations can appear due to internal errors during DNA replication
and cell division or as a consequence of exposure to external factors
(carcinogens)
̶ physical – e.g. UV and ionizing light
̶ chemical – organic substances, toxins, heavy metals
̶ biologic – some RNA and DNA viruses
Epigenetic alterations can contribute to the acquisition of hallmark
capabilities during tumor development and malignant progression.
̶ hypoxia-mediated epigenetic changes
̶ the acidic tumor microenvironment-mediated epigenetic changes
̶ extracellular matrix (ECM) motifs
PC-3 prostate cells, quantitative phase imaging, 10X
•10.1089/ars.2010.3368
single DNA strand breakdouble DNA strand break
5000/cell cycle50/cell cycle
30 000 000 000 000 breaks/day in human
Double strand breaks – most serious DNA damage
repair of 1 double strand
break = 104 ATP molecules
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DNA repair genes/proteins
MMR genes/proteins (“Mismatch repair”)
defect in respective genes leads to the microsatellite instability (MSI). Variable
length of microsatellites (e.g. (CA)n repetition) leads to the DNA replication errors.
MSI is most prevalent in colon cancers.
Nucleotide excision repair genes/proteins (“single strand break repair”)
NER-defects cause xeroderma pigmentosum (XP). XP patients show severe sun
sensitivity and develop skin cancers during childhood.
Genes/proteins of homologous recombination (“ double strand break repair ”)
̶ BRCA1 and BRCA2 "breast cancer susceptibility genes"
̶ ATM and ATR (ATM-related) kinases ("mutated in ataxia-telangiectasia")
̶ reciprocal relationship between cancer cells and components of the
TME
̶ Tumor cells stimulate significant molecular, cellular and physical changes
within their host tissues to support tumor growth and progression.
̶ Cancer cells recruit stromal cells from neighboring tissue during
tumorigenesis.
̶ TME includes immune cells, stromal cells, blood vessels, and extracellular
matrix (ECM) and can have an anti-tumor or pro-tumor effects.
̶ The stromal cell composition varies between tumor types but includes
endothelial cells, fibroblasts, adipocytes, and stellate cells. The TME
orchestrates angiogenesis, proliferation, invasion, and metastasis through
the secretion of growth factors and cytokines.
̶ Acidic metabolic waste products accumulate in the tumor microenvironment
because of high metabolic activity and insufficient perfusion. The pH of
TME influences cancer and stromal cell function, their mutual interplay, and
their interactions with the ECM.
Tumor microenvironment
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• There are important similarities between
tumors and the inflammatory response
associated with wound healing
• “Tumors: Wounds that do not heal”.
• Many cancers arise from sites of infection,
chronic irritation, and inflammation.
• Chronic inflammation can cause DNA
damage and permanent activation of
fibroblasts.
Inflammation
Inflammation and obesity
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̶ As people become obese more fat cells are build up in their
tissues and macrophages are recruited to clear up dead fat cells.
The number of macrophages in obese fatty tissue can be
substantial– 4 in 10 cells. Macrophages release cocktail of
cytokines that can trigger chronic inflammation.
̶ Obese people tend to have higher levels of inflammatory cytokines
in their blood.
̶ Fat isn’t just padding: it’s like another organ that is essentially a
huge gland sending out biological information that affects the rest
of the body. Oestrogen and growth factors produced by fat cells
increase the risk of cancer.
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Polymorphic microbiomes
̶ The evidence is increasingly compelling that polymorphic variability in the microbiomes between individuals in a population
can have a profound impact on cancer phenotypes.
̶ There are both cancer-protective and tumor-promoting microbiomes, involving particular bacterial species, which can
modulate the incidence and pathogenesis of tumors.
̶ A mouse model of colon carcinogenesis populated with bacteria Porphyromonas developed more tumors than mice lacking
such bacteria.
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Hallmarks of cancer
All these features do not have to be newly evolved, because
they are part of physiological processes such as
embryogenesis and wound healing. Cancer cells only use
these processes at the wrong intensity, time, and place.
Cancer is a disease of regulation.
̶ Continual upregulated proliferation of cancer cells (sustaining
proliferative signaling and evading growth suppressors)
̶ Replicative immortality
̶ Genome instability
̶ Resisting cell death and senescence
̶ Inducing angiogenesis
̶ Inflammation
̶ Avoiding immune destruction
̶ Altered metabolism
̶ Invasion and metastasis
Cancer cell
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Cancer cells divide excessively - they have too many “GO” signals or not enough “STOP” signals and
can also ignore “DIE”, “ DIFFERENTIATE “, or “GROW OLD” signals.
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Oncogenes and tumor suppressors
̶ Proto-oncogenes – Genes whose products encode
components of the molecular cascades that mediate cell
growth, cell survival, and block cell differentiation.
̶ The abnormal, mutated form of the proto-oncogenes
that lead to excessive cell proliferation and cancer are
called oncogenes.
̶ Proteins encoded by tumor suppressor genes inhibit
cell proliferation or survival and support cell
differentiation.
Oncogenes
Oncogenes differ from proto-oncogenes in three basic ways:
1. timing and quality of expression
2. structure and function of protein products
3. degree to which their protein products are regulated by cellular signals
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Uncontrolled growth - “GO” signals
“GO” signals = main mitogenic signals include:
1. growth factors (e.g. EGF, VEGFA, PDGF)
2. growth factor receptors (e.g. the receptors for
epidermal growth factor EGF (EGFR) and its close
homologue HER2/neu (ERBB2)
3. receptor-coupled signal transduction molecules
(RAS family)
4. proteinkinases (SRC,ABL)
5. transcription factors (MYC, MYB, FOS, JUN)
6. cyclins
7. cyclin-dependent kinases (cdk)
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Contact inhibition and immortalization
̶ Proliferation of many normal cells is inhibited by cell-cell contact
(contact inhibition) and by erosion of telomeres (Hayflick limit), but
cancer cells are characteristically insensitive to such inhibition of
growth.
̶ Most pre-malignant cells escape from Hayflick limit by stabilizing their
telomeres (telomerase, hTERT).
̶ Cells that have stabilized their telomeres can proliferate indefinitely and
are therefore said to be immortalized. Immortal cells are not
necessarily transformed (tumorigenic) cells.
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Uncontrolled growth – loss of “STOP” signals
̶ The critical decisions concerning growth versus quiescence are made in the G1 phase of the cell cycle.
̶ Growth of normal cells is controlled by signals from the external environment (extracellular matrix, surface of
adjacent cells) and from the inside of the cell (DNA damage, cell damage, mitotic spindle damage).
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Tumor suppressors
̶ tumor suppressor proteins inhibit the same cell regulatory pathways that are stimulated by the products of
oncogenes.
̶ Most familial cancer syndromes are inherited as a recessive trait and correspond to the constitutive
inactivation of an important tumor suppressor gene.
̶ In many tumors suppressors are lost or inactivated.
Tumor suppressors are often named according to the type of tumor developing due to their loss of function.
Rb (= retinoblastoma)
WT (= Wilm’s tumor)
NF1 and NF2 (= neurofibromatosis)
APC (= Adenomatous Polyposis Coli)
DCC (= Deleted in Colon Cancer)
VHL (= von Hippel-Lindau syndrome)
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p53 – the guardian of the genome
Located at ch. 17p13
̶ “guardian of the genome” – active in G1 and G2 checkpoints
̶ DNA damage increases expression of p53
̶ acts as a transcription factor for DNA repair, apoptosis and
other genes
̶ Li-Fraumeni syndrome – inherited TP53 mutation
Inhibitors of cyclin-dependent kinases (e.g. p21, p16, etc.)
̶ p21 is the main target of p53 = inhibitor of Cdk – cell cycle
arrest in G1 phase by inhibition of Cdk2/cyclin E complex
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Rb protein–true tumor suppressor
̶ Rb is a main inhibitor of the cell cycle and controls the transition from G1- to S-phase.
̶ Rb inhibits the transcription factor E2F, which upon release from Rb ↑ expression of S phase genes (e.g. DNA replication
enzymes).
Rb is present all the time, its activity is
modulated by phosphorylation.
– phosphorylated Rb =inactive
– dephosphorylated Rb=active
Rb mutations are also involved in tumors of
adults (bladder, breast, and lung
carcinomas).
The significance of the Rb tumor suppressor
gene thus extends beyond retinoblastoma.
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Percentage of tumors with mutated p53
HPV and p53
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̶ The E6 viral protein expressed by HPV specifically binds to the p53 protein and induces its degradation.
This observation explains the rarity of p53 mutations in HPV-positive cervical cancers.
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Cell death
• Apoptosis
̶ Active (=needs energy), programmed cell death. The action of caspases and other
apoptotic enzymes (proteases and nucleases) leads to cell fragmentation to apoptotic
bodies that are removed by macrophages.
• Necrosis
̶ Accidental cell death caused mainly by external factors (temperature, pH). Cellular
content is released into the environment and damage surrounding tissues. Necrosis has
pro-inflammatory and tumor-promoting potential.
• Regulated necrosis
1. Necroptosis (driven by kinases RIP1 and RIP3).
2. Ferroptosis (dependent on iron and characterized by the accumulation of lipid
peroxides).
3. Parthanatos (dependent on the activity of poly (ADP-ribose)-polymerase (PARP)).
4. MPT-driven necrosis (induction of the mitochondrial membrane permeability
transition (MPT), can lead to mitochondrial swelling and cell death).
5. Pyroptosis (Pyroptosis is an inflammatory cell death usually caused by microbial
infection, accompanied by activation of inflammasomes and maturation of proinflammatory
cytokines interleukin-1β and interleukin-18. Proteins from Gasdermin family
are the executors).
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Apoptosis
̶ Apoptosis is the first described form of programmed cell death, and it plays a critical role in tissue homeostasis.
̶ It contributes to cell turnover, the proper functioning of the immune system, and embryonic development.
̶ There are several key characteristics of apoptosis:
cellular, organelle, and DNA fragmentation and formation of apoptotic bodies
active, energy consuming process executed by a subset of cellular proteins
Even though, in general, this process is immunological silent, apoptosis has been shown to be involved in
inflammatory pathologies as well.
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Apoptosis
There are two (or 3) major pathways that mediate apoptosis: intrinsic and extrinsic pathways.
The third modality of apoptosis induction is cell‐based.
Cytotoxic T cells can engage cells that present
non‐self‐antigens leading to cell death induction by
proteases called granzymes.
All apoptotic pathways converge on the central proteases
of this pathway: caspases, which are either playing a role
in transmitting cell death stimulus (initiator caspases) or
in the execution (effector caspases).
Intrinsic apoptosis is controlled by the equilibrium of the different Bcl‐2 (B‐cell
lymphoma 2) family members which can be disrupted by various stimuli leading to
cell death.
During extrinsic apoptosis, TNF (tumor necrosis factor) superfamily (TNFSF) can induce cell death by binding to their
cell surface receptors and activating a deathly signaling cascade causing extrinsic apoptosis.
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• Non-lytic cell death, apoptosis
(the integrity of plasma
membrane is sustained).
• Plasma membrane rupture
(PMR) is the final cataclysmic
event in lytic cell death
(regulated or accidental
necrosis).
• PMR releases intracellular
molecules known as damageassociated
molecular patterns
(DAMPs) that propagate the
inflammatory response.
Immunogenicity of different types of cell death
Bedoui, S., Herold, M.J. & Strasser, A. Emerging connectivity of programmed cell death pathways and its physiological implications. Nat Rev Mol Cell Biol 21, 678–695 (2020). https://doi.org/10.1038/s41580-020-0270-8
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Immunogenicity of different types of cell death
• The loss of plasma membrane integrity that occurs during regulated necrosis leads to the release of molecular damageassociated
molecular patterns (DAMPs) into the extracellular space.
• During necroptosis, anti-inflammatory cytokines (IL33) may be released in a specific context. IL33 promotes the
recruitment of regulatory T-lymphocytes to the intestinal mucosa, which may limit immunogenic response in necroptosis.
• In contrast, during ferroptosis or MPT-driven necrosis, no active production of cytokines or immunomodulatory factors has
been described that could attenuate the immunogenic effect of DAMPs.
• The most immunogenic form of regulated necrosis is pyroptosis, which involves the active production of proinflammatory
cytokines (IL-1β, IL-18) leading to the systemic inflammatory response.
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Resisting apoptosis
Tumor cells evolve a variety of strategies to limit
cell death.
Most known are:
̶ increased expression of antiapoptotic
regulators (Bcl-2, Bcl-xL) and survival signals
(insulin-like growth factors; Igf1/2)
̶ downregulating of proapoptotic factors (Bax,
Bim, Puma)
̶ loss of p53
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Resisting apoptosis
Chromosomal translocation associated with B-cell lymphomas.
The Bcl-2 gene is translocated behind a potent immunoglobulin gene promoter. Increased expression of Bcl-2 gene
is associated with inhibition of apoptosis.
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Resisting cell death by cell fusion
̶ opportunistic behavioral
patterns (cell fusion)
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Resistance to anoikis
̶ Anoikis is a form of programmed cell death that
occurs in anchorage-dependent cells when they
detach from the surrounding extracellular matrix.
̶ barrier to metastasis
̶ circulating tumor cells are anoikis resistant
̶ TrkB (neurotrophic receptor) overexpression
protects disseminated, circulating tumor cells from
undergoing anoikis.
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Inducing angiogenesis
̶ Like normal tissues, tumors need nutrients and oxygen.
̶ Tumor without blood circulation grew to 1–2 mm3. In the
absence of vascular support, tumors may become
necrotic.
̶ Up-regulation of the activity of angiogenic factors is not
sufficient for angiogenesis of the neoplasm. Negative
regulators of vessel growth need to be downregulated.
̶ New vessels enable the invasion of tumor cells into
circulation and the creation of distant metastases.
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Inducing angiogenesis
̶ Cells of the innate immune system
(macrophages, neutrophils, mast cells,
and myeloid progenitors) can infiltrate
premalignant lesions and contribute to
tumor angiogenesis.
̶ Vascular endothelial growth factor (VEGF)
production by stromal fibroblasts plays an
important role in tumor angiogenesis.
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Evading immune destruction
̶ Defective antigen presentation due to down-modulating
antigen-presenting machinery (↓ major histocompatibility
complex, MHC).
̶ Immune suppression in the tumor microenvironment,
mediated by CD4+CD25+ FoxP3+ regulatory T cells
(Tregs), or other types of suppressive cells.
̶ Paralyzing cytotoxic T lymphocytes (CTLs) and natural
killer (NK) cells via production of immuno-suppressive
cytokines (by the cancer cells or by the non-cancerous cells
in the tumor microenvironment). TGF-β is a chief mediator
of this activity.
̶ Down regulation of death receptors prevents death
ligand-mediated killing of tumor cells by both CTLs and NK
cells.
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Altered metabolism of cancer cells
̶ the ability to acquire necessary nutrients from a nutrient-poor (low glucosis)
and hostile (hypoxia, oxidative stress) environment and utilize these nutrients
to maintain viability and build new biomass.
̶ cancer-associated metabolic reprogramming have profound effects on gene
expression, cellular differentiation, and the tumor microenvironment.
̶ These adaptations involve an ability to access normally inaccessible nutrient
sources.
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Hallmarks of cancer metabolism
(1) deregulated uptake of glucose and amino acids
(Warburg effect, glutaminolysis)
(2) use of opportunistic modes of nutrient acquisition
(cannibalism)
(3) use of glycolysis/TCA cycle intermediates for
biosynthesis and NADPH production
(4) increased demand for nitrogen
(5) alterations in metabolite-driven gene regulation –
metabolites influence enzymes involved in deposition
and removal of epigenetic marks.
(6) metabolic interactions with the microenvironment
(lactate, tomor acidosis)
Altered metabolism
̶ Two principal nutrients that support survival and biosynthesis are glucose and glutamine.
̶ Glutamine provides the nitrogen required for the biosynthesis of purine and pyrimidine nucleotides and nonessential amino acids.
̶ Warburg effect - a markedly increased consumption of glucose by some tumors in comparison to the nonproliferating normal
tissues.
̶ Positron emission tomography (PET)-based imaging of the uptake of a radioactive fluorine-labeled glucose analog, 18Ffluorodeoxyglucose
(18F-FDG) has been successfully used in the clinic for tumor diagnosis.
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Metabolic interactions with the microenvironment
̶ Cancer cells alter the chemical composition of the
extracellular milieu, which exerts pleiotropic
effects on the phenotypes of normal cells that
reside in the vicinity of the tumor.
̶ Reciprocally, the microenvironment affects the
metabolism and signaling responses of cancer
cells.
̶ The high metabolic demand of cancer cells leads
to an accumulation of H+ ions in the TME–
acidosis.
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Metabolic symbiosis
̶ Catabolic fibroblasts are a rich source of energy
and biomass for the growth and survival of
anabolic cancer cells.
̶ A linear path of clonal succession oversimplifies
the reality of cancer; a number of genetically
distinct subclones of cells coexist within a single
tumor mass: intra-tumor heterogeneity - oxidative
and glycolytic tumor cells in one tumor.
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Use of opportunistic modes of nutrient acquisition
̶ Ras or c-Src oncogenes allow to recover free amino
acids through the lysosomal degradation of
extracellular proteins.
̶ Macropinocytosis.
̶ Macroautophagy (autophagy cannot supply cells
with new biomass and thus cannot support
proliferation in nutrient-poor conditions).
̶ Phagocytosis of apoptotic cellular corpses.
̶ Cannibalism.
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Invasion and metastasis
̶ Cancer cells lose E-cadherin-dependent intercellular adhesions,
acquire a migratory phenotype (anoikis resistance, epithelialmesenchymal
transition=EMT), penetrate the basement membrane,
and invade the interstitial matrix (production of MMPs).
̶ Tumour angiogenesis allows cancer cells to enter the bloodstream
(circulating tumor cells), either directly or through the lymphatic
system, by a process called intravasation.
̶ In the circulation, tumour cells form small aggregates with platelets
and leukocytes.
̶ After stopping in the microcirculation of the target organ, tumour cells
exit the bloodstream, by a process called extravasation, and undergo
local expansion.
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Seed and soil hypothesis –permissive microenvironment
̶ Metastasis is dependent on the interactions between
'seeds' (the cancer cells) and the 'soil' (the host
microenvironment).
̶ Different cancers have preferential sites of
metastasis=organotropism (prostate cancer - the
bone and the liver).
̶ Tumour-secreted factors and tumor-shed
extracellular vesicles enable the 'soil' at distant
metastatic sites to encourage the outgrowth of
incoming cancer cells.
Pre-metastatic niches (PMNs) are sites of immune deregulation, owing to the presence of a pro-tumorigenic,
inflammatory milieu induced by tumor-secreted factors, which creates immunosuppression and coagulation
disorders.
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Cancer stem cell (CSC) hypothesis
̶ Cancer stem cells are rare immortal cells within a tumor that can both self-renew by dividing and give rise to
many cell types that constitute the tumor.
̶ CSCs are responsible for tumor initiation and growth.
̶ CSCs are associated with metastasis and relapse.
̶ Enhanced resistance to therapy and cell stress.
̶ Such cells have been found in various types of human tumors and might be attractive targets for cancer
therapy.
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Tumor clasification
̶ the most common human cancers are of epithelial origin—carcinomas.
̶ two main categories: squamous cell carcinomas (from epithelia that
form protective cell layers) and adenocarcinomas (from secretory
epithelia).
̶ Nonepithelial malignant tumors include sarcomas (from mesenchymal
cells); hematopoietic cancers (from the precursors of blood cells); and
neuroectodermal tumors (from components of the nervous system).
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Tumor clasification
̶ If a tumor’s cells have dedifferentiated (lost all tissue-specific traits), its origin can not be readily identified; such
tumors are said to be anaplastic.
̶ Benign tumors may be hyperplastic or metaplastic. Hyperplastic tissues are normal except for an excessive
number of cells, whereas metaplastic tissues show displacement of normal cells by normal cell types not usually
encountered at that site.
̶ Dysplastic tumors contain cells that are cytologically abnormal. Dysplasia is a transitional state between completely
benign and premalignant.
̶ Adenomas, polyps, papillomas, and warts are dysplastic epithelial tumors that are considered to be benign
because they respect the boundary created by the basement membrane.
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Tumor clasification
̶ typing = histological type
̶ grading = benign × malignant
̶ staging = TNM classification (T = tumor, N =
node, M =metastasis)
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local effect of tumor
Interaction of tumor with the host
̶ mechanical compression (eg. brain tumors)
̶ obstruction (e.g. carcinoma of the ductus choledochus)
̶ bleeding, bruise (leukaemia)
̶ chronic blood losses into GIT (gastric and intestinal tumors)
̶ oedema (e.g. lymphomas)
̶ coughing (lung carcinoma)
̶ thromboses
̶ difficult swallowing (oesophageal ca)
̶ loss of vision (compression of optic nerve by hypophyseal
adenoma)
̶ voice changes (laryngeal carcinoma)
̶ pathological fractures (myeloma)
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systemic effects of tumor
Interaction of tumor with the host
̶ anemia (suppression of bone marrow) – effect of proinflammatory cytokines
̶ fever - production of cytokines (pyrogens) by tumor (IL-1, TNFα)
̶ tumor cachexia – anorexic mediators (TNFα)
̶ paraneoplastic syndromes – some tumors produce hormones (adenomas); important
diagnostically!
–pigmentation
–endocrinopathy (Cushing sy., hypercalcemia).
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Cancer biomarkers
̶ Cancer biomarkers are substances that are produced in response to
cancerogenesis.
̶ These substances can be found in the tumor tissue, stool, blood, urine, or
other bodily fluids.
̶ Most cancer biomarkers are proteins. However, patterns of gene expression
(mRNA, miRNA) and changes in DNA can be used (SNPs, mutations).
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Cancer biomarkers
Cancer biomarkers can be classified into the categories based on their
usage:
̶ Predictive biomarkers predict response to specific therapeutic interventions
(positivity/activation of HER2 that predicts response to trastuzumab in breast
cancer).
̶ Prognostic biomarkers aim to inform regarding the risk of clinical outcomes
such as cancer recurrence or disease progression.
̶ Diagnostic biomarkers are used to identify whether a patient has a specific
disease.
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Cancer biomarkers – clinically relevant examples
Alpha-fetoprotein (AFP)
̶ Cancer types: Liver cancer and germ cell tumors
̶ Tissue analyzed: Blood
̶ How used: To help diagnose liver cancer and follow response to treatment; to assess stage, prognosis, and response to treatment of
germ cell tumors
BCR-ABL fusion gene (Philadelphia chromosome)
̶ Cancer type: Chronic myeloid lukemia, acute lymphoblastic leukemia, and acute myelogenous leukemia
̶ Tissue analyzed: Blood and/or bone marrow
̶ How used: To confirm diagnosis, predict response to targeted therapy, and monitor disease status
Cencer antigen (CA) 15-3
̶ Cancer type: Breast cancer
̶ Tissue analyzed: Blood
̶ How used: To assess whether treatment is working or disease has recurred
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Cancer biomarkers - examples
HER2/neu gene amplification or protein overexpression
̶ Cancer types: Breast cancer, gastric cancer
̶ Tissue analyzed: Tumor
̶ How used: To determine whether treatment with certain targeted therapies is appropriate
Prostate-specific antigen (PSA)
̶ Cancer type: Prostate cancer
̶ Tissue analyzed: Blood
̶ How used: To help in diagnosis, assess response to treatment, and look for recurrence
Carcinoembryonic antigen (CEA)
̶ Cancer types: Colorectal cancer and some other cancers (lung, breast)
̶ Tissue analyzed: Blood
̶ How used: To assess response to treatment, and look for recurrence
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