Summary Mechanisms of Disease 2: Full Overview

MVD


LEARNING OBJECTIVES MOD2
THEME 1A: CANCER BIOLOGY & GENETICS

Explain the processes that initiate and influence cancer development
and relate these processes to the phenotypical characteristics of cancer, patient
clinical
outcomes, and the impact on treatment strategies.
 Processes that Initiate and Influence Cancer Development
o Genetic Mutations
 Initiating events
 Mutation of DNA in cell
 Inherited: germline
 Acquired: somatic
 Environmental exposure: smoking, UV
 Errors in DNA replication
 Viral infections, e.g., HPV
 Types of genetic changes
 Oncogenes
 Mutated forms of normal genes, proto-
oncogenes, which drive uncontrolled cell
proliferation
 E.g., HER2 in breast cancer
 Tumor suppressor genes
 Normally inhibit cell growth or induce apoptosis
 Mutated form cannot inhibit anymore
 Loss-of-function mutations
 p53
 DNA repair genes
 Mutations lead to impaired ability to repair
damaged DNA, leads to further mutations
 BRCA1/2
o Epigenetic Mutations
 DNA methylation & histone modification
 Alter expression without DNA modifying
 Hypermethylation in tumor suppressor promoters can
lead to silencing, contributing to cancer
o Cellular Microenvironment
 Tumor microenvironment
 Comprises surrounding stromal cells, immune cells,
blood vessels, and signaling molecules
 Interaction between tumor and TME supports tumor
growth, angiogenesis, and immune evasion
 Chronic inflammation
 Persistent inflammatory response can promote
carcinogenesis by generating reactive oxygen species
(ROS)
 ROS damage DNA and create a pro-tumorigenic
environment
o Clonal Evolution &
Heterogeneity
 Clonal selection &
competition


1



Figure 1: Clonal cooperation

, MVD



Mutations accumulate  some cells acquire selective
advantages  dominate tumor mass
 Intertumoral heterogeneity
 Genetic diversity within tumor allows for adaptation to
environmental pressures  therapy resistance
 Phenotypical Characteristics of Cancer
o Uncontrolled Proliferation
 Cause
 Activation of oncogenes
 Loss of tumor suppressor gene function
 Clinical implication
 Rapid tumor growth
 Potential spread: metastasis
o Resistance to Cell Death
 Cause
 Mutations in genes regulating
apoptosis
 Expression of anti-apoptotic
proteins
 Clinical implication
 Tumors can persist despite the
body’s natural mechanisms to
eliminate abnormal cells
o Sustained Angiogenesis
 Cause Figure 2: Resistance to Cell Death
 Pro-angiogenic factors (e.g.,
VGEF) secreted by tumors
 Ensure adequate blood supply
 Clinical implication
 Facilitates tumor growth
 Facilitates metastasis
 Angiogenesis inhibitors can be used as treatment
o Tissue Invasion & Metastasis
 Cause
 Epithelial-mesenchymal transition (Weinberg), cancer
cells acquire ability to migrate and invade other tissues
 Table 1: Characteristics
Epithelial Mesenchymal
Cell polarity No cell polarity
Cell adhesion: to Loss of cell adhesion
each other and ECM
Stationary Ability to migrate and
invade
High level of E- Low level of E-cadherin
cadherin
Low level of N- High level of N-
cadherin cadherin


Clinical implication
 Metastasis
o Genomic Instability
 Cause
 Impaired DNA repair mechanisms
 Clinical implication

2

, MVD


 Genetic diversity within tumor
 Drives evolution and resistance to therapy
o Evasion of Immune Surveillance
 Cause
 Cancer cells can evade immune system by
downregulating antigen presentation or expressing
immune checkpoint proteins (e.g., PD-L1)
 Clinical implication
 Immunotherapies can block checkpoints  helps
restore immune activity against cancer
 Relation to Clinical Outcome
o Aggressiveness of the Tumor
 High proliferative rates and metastatic potential  worsen
prognosis
 Genomic instability and tumor heterogeneity  poor
responses to standard treatments
o Biomarkers & Predictive Factors
 Genetic mutations or protein expression levels can be used to
predict the likely course of the disease and guide targeted
therapy
o Stage at Diagnosis
 Early-stage detection has generally better outcome than
advanced stage detection
 Impact on Treatment Strategies
o Targeted Therapies
 Action
 Target specific molecular alterations
 Challenges
 Resistance may develop
o Immunotherapies
 Action
 Utilize the body’s immune system to recognize and kill
cancer cells
 Immune checkpoint inhibitors
 Challenges
 Not all patients respond
 Immune-related side effects
o Chemotherapy & Radiation
 Action
 Target rapidly dividing cells
 Induce DNA damage
 Challenges
 Nonselective
 Effects normal cells, causing side effects
 Tumors with DNA repair defects may be more sensitive

o Epigenetic Therapies
 Action
 Reverse abnormal epigenetic changes in cancer cells
 Challenges
 Still in development
 Variable efficacy
o Combination Therapy
 Rationale

3

, MVD


 Combining therapies may overcome resistance
 Achieve better clinical outcomes


Distinguish the roles of genetic and environmental factors in increasing cancer
risk, associate specific etiological factors (e.g., gene defects, oncogenic viruses)
with the
development of specific cancer types, and propose preventive strategies for
specific at-
risk populations.
 Roles of Genetic & Environmental Factors in Cancer Risk
o Genetic Factors
 Germline mutations (inherited)
 Present in every cell from birth
 Can be passed on to offspring
 5-10% of all cancers
 Examples
 BRCA
 MLH1, MSH2, MSH6, PMS2  Lynch
 Family history
 Strong family history of cancer suggests a higher risk to
develop cancer due to shared genetic mutations or
family-wide exposure to carcinogens
 Genetic syndromes
 Certain hereditary syndromes predispose individuals for
the development of cancer
 Examples
 Lynch syndrome
 Li-Fraumeni syndrome
o Environmental Factors
 Lifestyle choices
 Smoking
 UV
 Alcohol consumption
 Poor diet
 Physical inactivity
 Obesity
 Carcinogens
 Chemical exposure
 Asbestos, benzine, etc.
 Radiation
 UV, radon, etc.
 Air pollution

 Infectious agents
 Oncogenic viruses
 HPV
 Hep B/C
 Hormones
 Association of Specific Etiological Factors with Cancer Types
o Gene Defects
 BRCA1/2 mutations
 Associated cancers
 Breast

4