Cancer cell
biology
Michalina Janiszewska
Cell Bio Class 2020
• Identify cellular features associated with
tumorigenesis
• Identify differences between cancer cells and normal
cells that could be used for therapeutic approach
Objectives
• Give examples of cell-based mechanisms targeted by
current anti-cancer treatment
• Identify cell-based mechanisms related to anti-cancer
drug toxicities
• Discuss new emerging therapeutic approaches in
oncology
https://www.uicc.org/news/new-global-cancer-data-globocan-2018
Cancer death rates are declining,
but not for all cancer types
seer.cancer.gov
Cancer incidence (in 2016 in UK)
The diagnosis
SYMPTOMS
IMAGING
BIOPSY
The diagnosis - distorted tissue morphology
http://library.med.utah.edu/WebPath/FEMHTML/FEM008.html
http://sphweb.bumc.bu.edu/otlt/MPH-Modules/PH/PH709_Cancer/PH709_Cancer7.html
The hallmarks of cancer
Hanahan & Weinberg, Cell 2000, 2011
Genome instability and mutation – the origin of cancer
Classic view of tumorigenesis:
• Random mutations accumulate
and alter cellular phenotype
• This leads to overcoming barriers
to uncontrolled proliferation
(this has been recently challenged, as oncogenic
mutations are found in normal cells)
Yzhak et al., 2019 Science
Martincorena & Campbell, Science 2015
Zhu et al., Cell 2019 (and many more!)
First tumorigenesis model: Fearon & Vogelstein, Cell 1990
Genome instability and mutation
In normal cells multiple
mechanisms maintain
genome stability
Prakash et al, Molecules MDPI 2018
Genome instability and mutation
Cancer cells can
potentially have
multiple defects leading
to genomic instability
To become transformed cells
have to make it through this
decision point
Prakash et al, Molecules MDPI 2018
Genome instability and mutation
Aneuploidy – abnormal genomic state (DNA content ≠ 2𝑁 )
Chromosomal Instability
• Gain or loss of whole chrmomosome (W-CIN)
• Structural aberration (S-CIN)
• Point mutations
• Small scale or whole arm chromosomal
rearrangements
Weinberg, TheBiology of Cancer
Mechanisms leading to
polypoloidy
A. formation of polyploid cells can result from cytokinesis
failure due to entosis;
• cannibalism by entosis requires E-cadherin–mediated
junctions (orange) between engulfing cells and their
targets, and cell uptake is driven by Rho and Rhokinase activity within internalizing cells that invade
into their hosts (orange arrow).
B. cytokinesis failure due to gene dysregulation;
C. endoreplication;
D. cell fusion.
E. binucleate or tetraploid cells often form multipolar spindles
in mitosis due to increased centrosome number.
F. subsequent divisions can be bipolar, but often with
merotelic chromosome attachments, resulting in
chromosome missegregation.
G. multipolar divisions result in gross aneuploidy, which is
often lethal but can lead to rare aggressive clones.
Krajcovic et al., Cancer Research 2012
Genome instability and mutation
Cost of aneuploidy/CIN:
• Increasing instability with every division
• Slower division
• Improper dosage of thousands of genes at
a time > dramatic expression changes >
high impact on cellular fitness (metabolism,
protein production, etc.)
Benefits of aneuploidy/CIN:
• Rapid exploration of complex genetic
makeups with multiple mutations at a time
Quick way to overcome selective
pressure – change in glucose levels,
hypoxia or a treatment
Sansregret et al, Nature Reviews Clinicla Oncology 2018
TUMOR EVOLUTION
Genome instability and mutation
Genomic instability may lead to generation of all hallmarks of cancer
DNA damage is also closely connected with other hallmarks
Negrini et al, Nat Rev Mol Cell Biol 2010
RESOURCE: cbioportal.org
Output of TCGA (The Cancer Genome Atlas)
TCGA: Exome seq, RNA
seq
>100 datasets with as
many as 10,000 cases
All different tumor
types
Great for exploring:
• Mutation frequency
in particular tumor
type
• Expression
correlation
• Mutation cooccurrence
• Subseting data by
mutation/expression
levels (some studies
with survival data
and tumor subtype)
Targeting genome instability
May hospitals and private foundations are working towards genetic profiling (exome or whole genome
sequencing) >> alteration-specific threapy choice
(more in Drug Discovery class)
Sustaining proliferation and evading growth suppression
Solid tumor = mass >> cells proliferating out of
control
(also true for hematologic malignancies)
Al-Janabi, PlosOne 2013
Sustaining proliferation and evading growth suppression
Cell cycle progression depends on mitogen signals (+) and DNA damage (-)
Otto & Sicinski, Nat Rev Cancer 2017
Sustaining proliferation and evading growth suppression
Normal cells proliferate due to growth factor stimulation
Cancer cells become growth-factor independent >> mutations in key pathways
Sustaining proliferation and evading growth suppression
Mutations in cell cycle checkpoint
components are very frequent in cancer
• Mitogen-independent growth
• Tolerance of DNA damage
Most common oncogenes and tumor
suppressor genes are also linked to cell
cycle & DNA damage control
Otto & Sicinski, Nat Rev Cancer 2017
Sustaining proliferation and evading growth suppression
Oncogenes:
For example, Ras point mutations triggering growth factor independent proliferation
Sustaining proliferation and evading growth suppression
Oncogenes:
For example, Ras point mutations triggering growth factor independent proliferation
Sustaining proliferation and evading growth suppression
Tumor suppresors:
For example, p53 point mutations disable cell cycle checkpoint, DNA repair and apoptosis
Sustaining proliferation and evading growth suppression
Tumor suppresors:
For example, p53 point mutations disable cell cycle checkpoint, DNA repair and apoptosis
Enabling replicative immortality
HeLa cell line in culture since 1951
Cancer cells adopt ES-like features
and proliferate infinitely in vitro
Enabling replicative immortality
Telomeres protect chromosomal ends from
fusing with each other
Telomeres shorten with every cell division –
determine cellular life-span
Telomerase – enzyme expressed in ES cells
responsible for elongation of telomeres
90% of human cancers overexpress
telomerase = immortality
(more details in Cancer Bio class – stay tuned)
Resisting cell death
There are several pathways to cell death – each one of them can be deregulated in cancer cells
Resisting cell death
Mutations in p53
Lower caspase
expression
Lower death receptor
expression
Increase expression of
antiapoptotic proteins
Increased expression
of IAPs
Resisting cell death
Mutations in p53
Lower caspase
expression
Lower death
receptor
expression
Increase
expression of
antiapoptotic
proteins
Increased
expression of IAPs
Deregulating cellular energetics
Changes in mitochondrial function are not only
important for evading apoptosis…
Metabolism in normal cells depends on
growth signals and nutrient abundance
Vander Heiden et al., Science 2009
Deregulating cellular energetics – the Warburg effect
Metabolism of cancer cells is often shifted towards biomass generation rather than ATP production, regardless of oxygen supply
Vander Heiden et al., Science 2009
Deregulating cellular energetics – the Warburg effect and cancer stem cells
https://stm.sciencemag.org/content/10/442/eaaq1011
Tumor induced inflammation vs immune evasion
Crusz & Balkwill, Nat Rev Clin Oncol 2015
Tumor-associated neoantigens
In theory, the more mutations a cancer cell has, the more diverse repertoire of
neoantigens
…but not all neoantigens are equal – some are not that immunogenic…
Yarchoan et al, Nat Rev Cancer 2017
Tumor induced inflammation vs immune evasion
Immunoediting – cancer cells with most
immunogenic phenotype are eliminated
Immunosuppression - cancer cells evolve
to downregulate immune activation
pathways and upregulation of
immunosuppressive pathways (PDL1,
IDO1, CTLA4 etc.)
Yarchoan et al, Nat Rev Cancer 2017
Immune checkpoint and immunotherapy
Lim et al, Nat Rev Clin Oncol 2018
Tumor induced inflammation vs immune evasion
Overall response rate for
PD1-PDL1 inhibition
correlates with mutation
frequency
Yarchoan et al, Nat Rev Cancer 2017
Immune treatment engineering based on neoantigen prediction
Yarchoan et al, Nat Rev Cancer 2017
Binnewies et al., Nat Med 2018
Invasion and metastasis
Shroeder et al., Nat Rev Cancer 2012
Invasion and metastasis
METASTATIC CASCADE
1. Acquisition of invasive
phenotype
2. Intravasation into blood vessel
3. Surviving in circulation
4. Extravasation to distant tissue
(pre-metastatic niche)
5. (possible dormancy or death)
6. Full-blown metastatic growth
Anderson et al., Nat Rev Clin Oncol 2019
Epithelial-to-mesenchymal transition (EMT) – invasion/metastasis phenotype
Janiszewska et al., JBC 2020
EMT – changes in cell adhesion, cytoskeleton organization >> more mesenchymal morphology, increased invasion
Epithelial-to-mesenchymal transition (EMT) – invasion/metastasis phenotype
https://www.nature.com/articles/ncb2976
Epithelial-to-mesenchymal transition (EMT) – invasion/metastasis phenotype
TAM – tumor associated macrophages
CAF – cancer activated fibroblasts
CTC- circulating tumor cells
EMT phenotype is a spectrum;
cancer cells can travel through vasculature as clusters! >> polyclonal
metastasis
Nieto et al., Cell 2016
Invasion – different modes of
migration – from single-cell to
collective migration
Distinct modes of cancer cell migration –
dependence on cell adhesion and tumor
microenvironment
Friedl & Alexander, Cell 2011
Molecular determinants of migration
(A) Cell surface receptors and adaptors that
mediate the dynamic interface between
the actincytoskeleton and promigratory signaling
and the extracellular matrix (ECM).
(B) Cell surface proteins that mediate and
regulate interactions between cells. Similar
adhesion mechanisms may mediate homotypic
cell-cell cohesion during collective invasion and
transient and more dynamic heterophilic
interaction to resident tissue cells encountered
during tissue invasion.
C) Protease systems upregulated in cancer
progression, invasion, and metastasis.
D) Receptors for chemokines, cytokines, and
growth factors, which sense soluble, ECM-, or
proteoglycan-bound factors and interaction
partners. Green symbols represent selected
intracellular adapters to the actin cytoskeleton,
as specified below the drawing (A and B); shaded
labels represent major signaling molecules
regulating actin organization and cell migration.
Friedl & Alexander, Cell 2011
Angiogenic switch
Most tumours start growing as avascular
nodules (dormant) (a) until they reach a
steady-state level of proliferating and
apoptosing cells.
The initiation of angiogenesis, or the
‘angiogenic switch’, has to occur to ensure
exponential tumour growth. The switch
begins with perivascular detachment and
vessel dilation (b), followed by angiogenic
sprouting (c), new vessel formation and
maturation, and the recruitment of
perivascular cells (d).
Blood-vessel formation will continue as
long as the tumour grows, and the blood
vessels specifically feed hypoxic and
necrotic areas of the tumour to provide it
with essential nutrients and oxygen (e).
Bergers & Benjamin, Nature Rev Cancer 2003
Hypoxia and necrosis activate angiogenic sprouting
Bergers & Benjamin, Nature Rev Cancer 2003
Inducing angiogenesis
Cancer cells can secrete angiogenic
factors:
VEGF
PDGF
bFGF
All these activate circulating precursor
endothelial cells from bone marrow
and stimulate vessel growth
Folkman, Nat Rev Drug Disc 2007
Blocking angiogenic pathways – limited effects
STAT3 & NF-kB –
transcription factors relying
on input from multiple
pathways sensing cytokines,
VEGF, reactive oxygen
species (ROS) and cellcell/cell-matrix interactions
All these factors can
contribute to increased
angiogenesis
Many of these pathways are
upregulated in cancer =
many alternatives for
treatment escape
Albini et al., Nat Rev Clin Oncol 2012
The hallmarks of cancer
Every malignant cell can
have a combination of
these traits, but not all
are required
Cancer cell >> cancer tissue
(different traits in different
cell populations can
contribute to cooperation)
Plasticity – adaptability - evolvability
Targeting hallmarks of cancer
Stay tuned – Drug discovery
lecture – Monday 2/24
@11.30am
New hallmark of cancer – tumor heterogeneity
Cancer Biology course coming in 2021