CANCER CELL BIOLOGY

LECTURE BY: DR. FRANCIS NIÑO ARCINAS CAÑEDO, MD, FPCP (HARRISON’S INTERNAL MEDICINE CHAPTER 68)
3RD YEAR, 2ND SEMESTER- ONCOLOGY MODULE

CANCER CELL BIOLOGY - CELL CYCLE CHECKPOINTS -

● Unregulated cell division, avoidance of cell death, tissue
invasion, and the ability to metastasize
● Epithelial: Carcinomas
● Mesenchymal: Sarcomas
● Hematopoietic: Leukemia, Lymphomas, Plasma cell
dyscrasias
● Monoclonal in origin
● Marked heterogeneity
● ONCOGENES
● Vast majority of human cancers are characterized by a
multiple step process involving many genetic
abnormalities
● Normal cells have a large number of safeguards against
DNA damage p53
● For most cancers, changes occur over a prolonged period ● Guardian of the genome
of time, usually MANY YEARS ● Transcription factor
● Activated once DNA damage is detected
● Normally bound to mdm2

● Abnormalities in the spindle checkpoint facilitate the

development of ANEUPLOIDY which is frequently found
in cancers
● In some tumors, aneuploidy is a predominant genetic
feature
● In general, tumors have defects in chromosome number
or defective DNA repair pathways BUT NOT BOTH
● Defects that lead to cancer:
○ Abnormal cell cycle checkpoints
○ Inadequate DNA repair
○ Failure to preserve genome integrity
● Human cancer become clinically detectable when a
primary mass is at least 1 cm in diameter (109 cells)
● A lethal tumor burden is about 10 12-1012 cells
● Gompertzian kinetics
CANCER CELL BIOLOGY 1
● The growth fraction of the first malignant cell is 100%, ● Telomerase
and estimated <10% if patients presents for medical ● More than 90% of human cancers express high levels
care of telomerase that prevent telomere shortening to
● Tumor is slowing its own growth over time critical levels and allow indefinite cell proliferation
● Tumor Microenvironment ● hTERT
● Telomere shortening

SIGNAL TRANSDUCTION PATHWAYS IN CANCER CELLS -

● Induction of activated transcription factors that mediate a change in cell behavior or function or acquisition of effector
machinery to accomplish a new task
● Kinases
○ TYROSINE KINASES
○ Serine/Threonine kinases
● Inhibition of kinase activity is effective in the treatment of a number of neoplasms
○ EGFR mutation: ERLOTINIB, IMATINIB
○ ALK, ROS1: CRIZOTINIB
○ BRAF mutations
○ JAK2
○ HER2: TRASTUZUMAB

CANCER CELL BIOLOGY 2

 CANCER-SPECIFIC GENETIC CHANGES - ● Epithelial Mesenchymal Transition
● Defects in DNA repair ● The rate-limiting step for metastasis is the ability for tumor
● Modifications in cell cycle control cells to survive and expand
● Enhanced survival mechanisms ● In the novel microenvironment of the metastatic site, and
● Tumor-stromal interactions multiple host-tumor interactions determine the ultimate
● Angiogenesis outcome
● The metastatic phenotype is likely restricted to a small
SYNTHETIC LETHALITY - fraction of tumor cells
● Cells with metastatic capability frequently express
● Occurs when loss of function in either two or more genes
chemokine capability frequently express chemokine
individually has limited effects on cell survival but loss of
receptors that are likely important in the metastatic
function in both (or more) genes leads to cell death
process
● Gene expression profiling
EPIGENETIC INFLUENCES ON CANCER GENE - ● BONE METASTASES and HYPERGLYCEMIA
TRANSCRIPTION -
● EPIGENETICS CANCER STEM CELLS -
● Epigenetic changes: ● Evidence seen in mice (AML and CML)
○ Alterations of chromatin structure ● They have undifferentiated phenotype, but are no longer
○ Modification of histones under homeostatic control
● The pattern of gene transcription is aberrant in all human ● Have unlimited proliferative capacity and paradoxically
cancers, and in many cases, epigenetic events are traverse the cell cycle at a slow rate
responsible ● Cancer growth: Expansion of stem cell pool, unregulated
● Epigenetic changes are potentially reversible and appear proliferation of an amplifying population, failure of
amenable to therapeutic intervention apoptosis pathways
● Epigenetic gene regulation can also occur via microRNAs ● Bcl-2 family, MDR family render cancer stem cells less
or long non-coding RNAs (IncRNA) vulnerable to chemotherapy or radiation therapy
● It's identification and isolation will allow determination of
APOPTOSIS AND OTHER MECHANISMS OF CELL- the aberrant pathways that distinguish these cells from
DEATH - normal tissue stem cells
● Programmed cell death
● Intrinsic Pathway: TNF PLASTICITY AND RESISTANCE -
● Extrinsic Pathway: cytochrome c & SMAC ● Allows to alter multiple aspects of cell biology in response
● Karyorrhexis to external factors
● The release of apoptosis-inducing proteins ○ Heterogeneity between different clones of cells
● From the mitochondria is regulated by pro- and ○ Tumor microenvironment
antiapoptotic members of the Bcl-2 family ● Malignancies have a WIDE spectrum of mechanisms for
initial and adaptive resistance to treatments
METASTASIS -
● Accounts for the vast majority of deaths from solid tumors CANCER METABOLISM -
● Initial step involves cell migration and invasion through the ● ALTERED METABOLISM
ECM ● GLUCOSE and GLUTAMINE
○ Cell adhesion to the basement membrane ● Many cancer cells utilize aerobic glycolysis ‘
○ Local proteolysis of the membrane ● pI3kinase and AMPK pathway
○ Movement of the cell through the rent in the ● Isocitrate dehydrogenases 1 and 2 (2HG)
membrane and the ECM
CANCER CELL BIOLOGY 3
 TUMOR MICROENVIRONMENT - EVASION OF THE IMMUNE SYSTEM BY CANCERS
● Inflammatory cells ● Downregulation in immune recognition
● ECM ● Expression of cell surface proteins that inhibit immune
● Secreted factors (growth factors) function
● Reactive oxygen and nitrogen species ● Secretion of proteins and other molecules that are
● Mechanical factors immunosuppressive
● Blood vessels ● Recruitment and expansion of immunosuppressive cells
● Lymphatics such as regulatory T cells
● IS NOT STATIC BUT RATHER IS DYNAMIC AND ● Induction of T cells tolerance
CONTINUALLY EVOLVING ● Downregulation of death receptors
● Immunotherapy
ANGIOGENESIS - ○ TX: Interferons, IL-2, monoclonal antibodies
● Blood is important for delivery of oxygen, nutrients, and ○ CD19 antigen
circulating factors important for growth and survival ○ CTLA-4
● Vascular endothelial cells
● ANGIOGENIC SWITCH
● Stimuli for tumor angiogenesis: hypoxemia,
inflammation, genetic lesions in oncogenes or tumpr
suppressors
● Tumor blood vessels are not normal; tortous and dilated,
excessive branching and shunting
● Tumor vessel walls have numerous openings
● Vascular mimicry
● Sprouting
● VEGFs: most potent trophic angiogenic
● Angiopoietins, ephrins
● Ang1
● Ang1/Tie2 pathway
● Ang2
● Lymphatic vessels also exist within tumors
○ VEGFR3, VEGF-C, VEGF-D
● Antiangiogenic Therapy
○ Bevacizumab, Ramucirumab, Ziv-aflibercept
● VEGF inhibitors: Hypertension

CANCER CELL BIOLOGY 4