j.gumulec@med.muni.cz1
Malignant transformation
Jaromír Gumulec
Dept. of Pathological Physiology
Faculty of Medicine, Masaryk University
Topics
Stages of tumor development
Theories of cancerogenesis
Hallmarks of cancer
Oncogenes and tumor suppressors
Metastases
Interaction of tumor and organism
Cancer biomarkers
Tumor development
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.
Theories of carcinogenesis
Somatic Mutation Theory (SMT)
• Changes in the DNA of the founder cell make this cell
unable to control its proliferation.
Tissue Organization Field Theory (TOFT).
• Carcinogenesis is “development gone awry.”
• Normal tissue blocks the proliferation and motility of cells,
leading to tissue homeostasis.
• Carcinogenesis is characterized by a disruption of the
normal tissue organization that 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.
Enabling
characteristics
of cancer
and cancer
hallmarks
• Genomic instability
• nonmutational epigenetic
reprogramming
• Tumor-promoting inflamation
Genomic instability and nonmutational 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 or ECM
stiffness-induced signaling
Genomic
instability–new
oportunities for
evolution
• DNA damage may predispose individuals to increased
tumorigenesis.
• An increase of copy number of chromosomes or
genes allows cells to overexpress certain genes or
mutate the extra copies to acquire growth, survival, or
invasion ability.
• Genomic instability is a characteristic of most cancer
cells due to over-replication.
• Excessive DNA damage is associated with problems in
DNA replication (broken chromosomes and aneuploidy).
• Genomic integrity is closely monitored by several
surveillance mechanisms, DNA damage checkpoint,
DNA repair machinery, and the mitotic checkpoint.
• DNA methylation status is also important for genomic
integrity.
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")
Unlocking phenotypic plasticity
Disruptions of cellular differentiation
Dedifferentiation from mature to progenitor states.
Suppressed expression of the MITF master regulator of
melanocyte differentiation is involved in the genesis of
aggressive forms of malignant melanoma.
Blocked (terminal) differentiation from progenitor cell
states
Acute promyelocytic leukemia can result from a
chromosomal translocation that fuses the promyelocytic
leukemia protein locus (PML) with the gene encoding the
retinoic acid α nuclear receptor (RARα). Myeloid progenitor
cells bearing such translocations are unable to differentiate
into granulocytes, resulting in cells trapped in a
proliferative, promyelocytic progenitor stage.
Transdifferentiation into different cell lineages.
The pancreatic acinar cells can become transdifferentiated
into a ductal cell phenotype during the initiation of
neoplastic development.
Tumor microenvironment
• Early in tumor growth, a dynamic and reciprocal relationship develops between cancer
cells and components of the tumor microenvironment.
• 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 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.
• The tumor ECM is typically characterized by increased cross-linking and density,
enzymatic modifications, and altered molecular composition, which collectively
orchestrate—in part via integrin receptors for ECM motifs—stiffness-induced
signaling and gene-expression networks that elicit invasiveness and other hallmark
characteristics.
• 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.
Inflammation
• 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.
Under normal conditions, the positive feedback loop (PFL) acts as a reversible bistable switch by which
the activation of fibroblasts is “ON" above a sufficient level of stimulation and “OFF" for the withdrawal of
the stimulus. However, this switch can be permanently turned on under pathologic conditions by
continued activation of the PFL, resulting in sustained proliferation of fibroblasts
Inflammation and
obesity
• 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–four 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 it is
essentially a huge gland sending out biological
information that affect the rest of body. Oestrogen
and growth factors produced by fat cells increase the
risk of cancer.
Senescent cells
• In addition to shutting down the cell cycle, the
senescence program evokes changes in cell
morphology and metabolism and, most profoundly,
the activation of a senescence-associated secretory
phenotype (SASP) involving the release of a plethora of
bioactive proteins, including chemokines, cytokines, and
proteases.
• SASP components can directly or indirectly promote
tumor cells growth, invasion and metastasis by
promoting tumor vascularization, maintaining stemcell
features, creating an immunosuppressive
environment, remodeling tissue structure, inducing
drug resistance, and stimulating epithelialmesenchymal
transition (EMT).
Polymorphic microbiomes
• For cancer, 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.
Hallmarks of cancer
• Continual unregulated 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
• 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 in wrong intensity, time, and
place. Cancer is a disease of regulation.
Cancer cell
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.
Oncogenes and tumor suppressors
Proto-oncogenes – Genes whose
products encode components of the
molecular cascades that mediate cell
growth, cell survival, and block cell
defferentiation.
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 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
Oncogenes
Uncontrolled growth
In cancer cells, a number of alternative mechanisms operate to ensure
that cell proliferation is not constrained.
Cancer cells produce growth factors that stimulate their own proliferation
(autocrine growth stimulation) and hijack cellular mitogenic signals.
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)
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.
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).
Tumor suppressors
• In many tumors are lost or inactivated.
• 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.
• 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)
“two hits” hypothesis explain the inheritance of retinoblastoma, a rare
childhood tumor type (1971, Knudsen)
Rb protein–true
tumor suppressor
• Rb is a main inhibitor of 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.
Will you be my tumor suppressor for ever?
• Tumor suppression is context-
dependent.
• TGF-β (transforming growth
factor- β) has an
antiproliferative effect and
maintains genomic stability. As
cancer progresses, tumor cells
alter their responsiveness to
TGF-β.
• At late-stage tumors, TGF-β
promotes cell migration,
invasion of cancer cells, and
becomes a pro-survival factor.
Other “ STOP“ signals
p53 protein (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 and apoptosis genes
inhibitors of cyclin-dependent kinases (e.g. p21, p27, 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
percentage of tumors with mutated p53
HPV and p53
• 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.
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 (infections, toxins, etc.).
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 pro-inflammatory cytokines interleukin-1β and interleukin-18.
Proteins from Gasdermin family are the executors).
APOPTOSIS
Immunogenicity of different types of cell death
• The loss of plasma membrane integrity that
occurs during regulated necrosis leads to the release
of molecular damage-associated molecular
patterns (DAMPs) into the extracellular space. During
necroptosis, anti-inflammatory cytokines (IL-33) may
be released in a specific context. IL-33 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 pro-inflammatory cytokines (IL-1β, IL-18)
leading to the systemic inflammatory response.
Resisting apoptosis
• Tumor cells evolve a variety of strategies to limit cell death. Most known are:
• loss of p53
• 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)
Resisting
apoptosis
Chromosomal translocation associated with Bcell
lymphomas.
The Bcl-2 gene is translocated behind a potent
immunoglobulin gene promoter. Increased epression of
Bcl-2 gene is associated with inhibition of apoptosis.
Resistence
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.
Resisting oncogene-induced senescence
• Cellular senescence is a growth-arrest
program that limits the lifespan of cells and
prevents unlimited cell proliferation.
• Certain mitogenic oncogenes or the loss of
anti-mitogenic tumour-suppressor genes
induce senescence. This is known as
oncogene-induced senescence.
• Many cancer cells either do not have fully
active senescence programs or develop
bypass mechanisms to regain proliferation
capabilities (c-myc overexpression).
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 invasion of tumor
cells into circulation and creation of
distant metastases.
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.
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.
Cancer Neoantigens: A Promising Source of
Immunogens for Cancer Immunotherapy
• Somatic mutations in tumor genes could be reflected in proteins. Missense or
frameshift mutation has the potential to generate tumor-specific antigens (TSAs),
which are theoretically recognized as “non-self” by the host immune system.
• TSAs, also known as “cancer neoantigens”, have the potential to be utilized as
biomarkers predicting clinical responses to immunotherapy and outcomes, as well as
serving as targets for immunotherapy.
• Neoantigens are also expressed by fetal organs. Older fetal organs (21 weeks) and
adult organs do not express an immunogenic neoantigens.
Oncological trogocytosis-the way how to get rid off
antigens
Intercellular exchange of intact
membrane patches.
Exchange of membrane
molecules/antigens.
Human epidermal growth factor
receptor 2 (HER2) could be
transferred from cancer cells to
monocytes via trogocytosis.
Altered
metabolism
• 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.
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, 18F-fluorodeoxyglucose (18F-FDG) has been
successfully used in the clinic for tumor diagnosis.
• Oncogenic signaling proteins—Ras upregulate GLUT1
mRNA expression and increase cellular glucose
consumption.
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.
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 tumor microenvironment –
acidosis.
Metabolic
symbiosis
Catabolic fibroblasts are 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;
number of genetically distinct subclones of cells coexist within a
single tumor mass: intra-tumor heterogeneity - oxidative and glycolytic
tumor cells in one tumor.
Invasion and metastasis
• Cancer cells lose E-cadherin dependent intercellular adhesions,
acquire a migratory phenotype (anoikis resistence, 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 proces called extravasation, and undergo
local expansion.
Migratory phenotype
• Cell migration can be classified into
single-cell migration modes
(mesenchymal, amoeboid) and
collective migration modes (cell
strands, sheets, clusters).
• These migration modes are
associated with cellular energetic
status, a characteristic structure of
the cytoskeleton, specific use of
integrins, matrix-degrading
enzymes, and cell-cell adhesion
molecules.
• Mesenchymal cell migration is a
motility mode characterized by the
elongated, spindle-like shape of
cells, high cell polarization, and in
the case of too-tight spaces in ECM,
by proteolytic ECM remodeling by
matrix metalloproteinases and
serine proteases. In migrating
cancer cells, mitochondria localize
at the leading edge to support
enhanced cell migration by
providing local sources of energy.
Invasion and metastasis
• Tumors that breach the basement membrane
and invade underlying tissue are malignant. An
even further degree of abnormality is
metastasis, the seeding of tumor colonies to
other sites in the body. Metastasis requires not
only invasiveness but also motility and
adaptation to foreign tissue environments.
• several ways of spreading:
• – blood (very often in the direction of flow from
GIT to the liver by venous blood to the lungs
from lungs by artery blood to bones and brain)
• – lymphatic (first neighboring lymph nodes,
then distant)
Seed and soil hypothesis –
permissive microenvironment
Tumor cell-intrinsic metastatic propensities are not sufficient for
metastatic seeding.
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 tumour-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 tumour-secreted factors, which
creates immunosuppression and coagulation disorders.
factors influencing organ-specific metastases to the liver, lung, brain,
bone and lymph nodes
Cancer stem cell
(CSC) hypothesis
Cancer stem cells are rare immortal cells within a tumor that can both selfrenew
by dividing and give rise to many cell types that constitute the tumor.
CSCs are tumorigenic, associated with metastasis and relaps.
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.
Tumor
clasification
the most common human cancers are of epithelial origin—
the 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).
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.
Tumor clasification
typing = histological type
grading = benign × malignant
staging = TNM classification (T =
tumor, N = node, M =metastasis)
Interaction of tumor with the host
local effect of tumor
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)
Interaction of tumor with the
host
systemic effects of tumor
anemia (supression of bone marrow) – effect of proinflammatory
cytokines
fever - production of cytokines (pyrrogens) by tumor (IL-1, TNFα)
tumor cachexia – anorexic mediators (TNFα)
paraneoplastic syndromes – some tumors produce hormones
(adenomas); important diagnostically!
–pigmentation
–endokrinopathy (Cushing sy.,hypercalcaemia).
Cancer biomarkers
Cancer biomarkers are substances that are produced in response to
cancerogenesis.
These substances can be found in the blood, urine, stool, tumor tissue, or
bodily fluids.
Most cancer biomarkers are proteins. However, patterns of gene
expression and changes in DNA can be used.
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.
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
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
Tissue analyzed: Blood
How used: To keep track of how well cancer treatments are working or check if cancer has come back
j.gumulec@med.muni.cz | @jarogumulec | www.med.muni.cz/masariklab