Chapter 11

Biology of Cancer
 Cancer

⬤Diseases in which abnormal cells divide

without control and are able to invade other
tissues
⬤Derived from Greek word for crab, karkinoma
⬤Tumor
⮚ Also referred to as a neoplasm—new growth
 Benign vs. Malignant Tumors

⬤Benign ⬤Malignant
⮚ Grow slowly ⮚ Grow rapidly
⮚ Encapsulated ⮚ Not encapsulated
⮚ Not invasive ⮚ Invasive
⮚ Well differentiated ⮚ Poorly differentiated
⮚ Low mitotic index ⮚ High mitotic index
⮚ Do not metastasize ⮚ Can spread distantly
(metastasize)
 Benign Tumors

⬤Named according to the tissues from which

they arise
⮚ Lipoma (fat cells)
⮚ Leiomyoma (smooth muscle of uterus)
⮚ Meningioma (meninges)
⬤May progress to cancer
 Malignant Tumors

⬤Named according to the cell type from which

they arise
⮚ Carcinoma (epithelial tissue)
⮚ Adenocarcinoma (ductal or glandular tissue)
⮚ Sarcoma (mesenchymal tissue)
⮚ Lymphoma (lymphatic tissue)
⮚ Leukemia (blood-forming cells)
 Carcinoma in Situ

⬤Early-stage cancers
⬤Preinvasive epithelial tumors of glandular or
squamous cell origin
⬤Have not broken through the basement
membrane or invaded the surrounding stroma
⬤Outcomes
⮚ Remain stable
⮚ Progress to invasive and metastatic cancers
⮚ Regress and disappear
 Question 1

1. Which of the following statements is TRUE?

A. All neoplasms are cancerous.

B. Benign growths are cancerous.
C. Malignant tumors have slow growth.
D. Cancer refers to a malignant tumor.

Note: No input needed to proceed

 Question 1 Answer

⬤Correct Answer: D

⬤Cancer refers to a malignant tumor. Benign

tumors, which are not invasive, are not
cancerous. Malignant tumors have rapid
growth. Neoplasms may be benign or
cancerous.
 Biology of Cancer Cells (1 of 2)

⬤Cancer is complex
⬤Tumor is a heterogenous mixture of cells
(cancerous and benign)
⬤Stages of cancer development
⮚ Tumor initiation
⮚ Tumor promotion
⮚ Tumor progression
 Biology of Cancer Cells (2 of 2)

⬤Multiple mutations are required before cancer

can develop
⮚ Driver mutations “drive” progression of cancer
⮚ After critical number of driver mutations, cell
becomes cancerous
⬤Clonal proliferation or expansion
⮚ Mutations cause cell to acquire characteristics that
give it selective advantage over its neighbors
• Increased growth rate or decreased apoptosis
 Hallmarks of Cancer (1 of 3)

⬤Primarily genomic alterations

⮚ Sustained proliferative signaling
⮚ Evading growth suppression
⮚ Genomic instability
⮚ Replicative immortality
⬤Secondary to genomic change
⮚ Angiogenesis
⮚ Reprogramming energy metabolism
 Hallmarks of Cancer (2 of 3)

⬤Tumor resistance to destruction

⮚ Resistance to apoptotic cell death
⮚ Tumor-promoting inflammation
⮚ Avoiding immune destruction
⬤Culmination of other hallmarks
⮚ Activating invasion and metastasis
Hallmarks of Cancer (3 of 3)

Adapted from Hanahan D, Weinberg RA: Cell 144:646, 2011.

 Sustained Proliferative Signaling (1
of 3)
⬤Foremost hallmark of cancer: uncontrolled
cellular proliferation
⮚ Normal cells in proliferative phases in response to
growth factors
⬤Proto-oncogenes
⮚ Genes that direct normal cellular proliferation
 Sustained Proliferative Signaling (2
of 3)
⬤Oncogenes
⮚ Mutated or overexpressed proto-oncogenes
⮚ Cause uncontrolled cell growth
⬤Autocrine stimulation
⮚ Ability of cancer to secrete growth factors that
stimulate their own growth
 Sustained Proliferative Signaling (3
of 3)
⬤Oncogene activation
⮚ Point mutation in RAS gene converts from
regulated to unregulated
⮚ Translocations
• Excess and inappropriate production of a proliferation
factor (Burkitt lymphoma)
• Production of novel proteins with growth promoting
properties (chronic myeloid leukemia)
• Gene amplification
Evading Growth Suppressors (1 of 2)

⬤Tumor-suppressor genes (anti-oncogenes)

⮚ Regulate cell cycle
⮚ Inhibit proliferation
⮚ Stop cell divisions if cells are damaged
⮚ Prevent mutations
Evading Growth Suppressors (2 of 2)

⬤Inactivation of tumor-suppressor genes

⮚ Allows unregulated cellular growth
• Retinoblastoma (RB) gene
• Tumor protein p53 (TP53)
⬤Humans have two copies of each tumor-
suppressor gene
⮚ Both copies must be inactivated in cancer
⮚ Two mutations are necessary
⮚ A single germ-cell mutation (sperm or egg) results
in transmission of cancer-causing genes
 Genomic Instability (1 of 2)

⬤Increased tendency for genomic mutations

during life cycle of the cell
⮚ Risk for cancer increases
⬤Caretaker genes
⮚ Encode for proteins that are involved in repairing
damaged DNA
⮚ Mutations increase genomic instability
 Genomic Instability (2 of 2)

⬤May result from increased epigenetic

silencing or modulation of gene functioning
⮚ Promoter regions of genes altered, leading to their
silencing or altered gene expression
⬤Chromosome instability
⮚ Increased in malignant cells
⮚ Results in chromosome loss, loss of
heterozygosity, and chromosome amplification
 Replicative Immortality (1 of 3)

⬤Normal body cells are not immortal and can

only divide a limited number of times
⬤Telomeres are protective caps on each
chromosome
⮚ Maintained and held in place by telomerase
• Usually only active in germ and stem cells
⮚ Block cell division and prevent immortality
⮚ Become smaller with each cell division
⮚ If become critically small, chromosomes fragment,
and cell dies
 Replicative Immortality (2 of 3)

⬤Cancer cells can activate telomerase

⮚ Restore and maintain telomeres
⮚ Unlimited division and proliferation
⮚ Telomerase activity restored in 90% of cancers
Replicative Immortality (3 of 3)
 Angiogenesis

⬤Growth of new blood vessels

⮚ Essential in tissue undergoing repair
⮚ Essential to growth and spread of cancer
⬤Cancerous tumors
⮚ Maintain secretion of angiogenic factors (VEGF)
⮚ Suppress angiogenesis inhibitors
Reprogramming Energy Metabolism
(1 of 2)
⬤Warburg effect
⮚ Use of glycolysis under normal oxygen conditions
(aerobic glycolysis)
⮚ Allows products of glycolysis to be used for rapid
cell growth
⬤Reverse Warburg effect
Reprogramming Energy Metabolism
(2 of 2)
⬤Oncogenes drive metabolic reprogramming
so cancer cells can:
⮚ Deregulate proliferation
⮚ Withstand oxygen and nutrient challenges
⮚ Remain dedifferentiated with alterations in gene
expression
⮚ Corrupt surrounding microenvironment to assist
tumor growth
 Resisting Apoptotic Cell Death

⬤Apoptosis is programmed cell death

⮚ Self-destruction
⬤Defects in intrinsic or extrinsic pathways
provides resistance to apoptotic cell death
Tumor-Promoting Inflammation (1 of
2)
⬤Chronic inflammation is an important factor in
the development of cancer
⮚ Some organs more susceptible to oncogenic
effects of inflammation
⮚ Successful tumors can alter inflammation to
benefit tumor growth
⬤Helicobacter pylori
⮚ Chronic inflammation associated with:
• Peptic ulcer disease
• Stomach carcinoma
• Mucosa-associated lymphoid tissue lymphomas
Tumor-Promoting Inflammation (2 of
2)
⬤Tumor-associated macrophage (TAM)
⮚ Key cells that promote tumor survival
⮚ Presence frequently correlates with a worse
prognosis
⮚ Mimic M2 phenotype
⮚ Have diminished cytotoxic response
⮚ Develop the capacity to block T-cytotoxic cell and
NK cell functions and produce cytokines that are
advantageous for tumor growth and spread
Evading Immune Destruction (1 of 3)

⬤Normal immune system protects against

cancer
⬤Tumor-associated antigens
⮚ Immune surveillance hypothesis—predicts
developing malignancies are suppressed by
efficient immune response
⮚ Immunotherapy—products immune system could
be used to target these antigens and destroy
tumors
Evading Immune Destruction (2 of 3)

⬤Tumor-infiltrating lymphocytes
⮚ Cancers actively recruit immune response
• Remodel tissues
• Form new blood vessels
• Promote metastasis
Evading Immune Destruction (3 of 3)

From Kumar V et al: Robbins and Cotran pathologic basis of disease, ed 9,

Philadelphia, 2015, Saunders.
 Activating Invasion and Metastasis

⬤Invasion
⮚ Local spread
⮚ Prerequisite for metastasis
⮚ Recruitment of TAMs is critical
⬤Metastasis
⮚ Spread of cancer from a primary site of origin to a
distant site
⮚ Changes in tumor microenvironment initiate
metastasis and cause cancer cells to evolve
• Epithelial-mesenchymal transition
 Epithelial-Mesenchymal Transition
(EMT)
⬤Model for transition to metastatic cancer cells
⬤Epithelial characteristics lost
⮚ Increased migratory capacity
⮚ Increased resistance to apoptosis
⮚ Dedifferentiated stem cell–like state
• Growth favored in foreign microenvironments
 Clinical Manifestations (1 of 2)

⬤Paraneoplastic syndromes
⮚ Symptom complexes triggered by cancer
⮚ Causes
• Biologic substances from tumor
• Immune response to tumor
• Not caused by direct local effects of tumor
⮚ Can be earliest symptoms of unknown cancer
 Clinical Manifestations (2 of 2)

⬤Cachexia
⮚ Multiorgan, energy wasting syndrome
⮚ Most severe form of malnutrition
⮚ Muscle weakness and fatigue
⮚ Altered protein, lipid, and carbohydrate
metabolism
⮚ Loss of white adipose tissue
⮚ Appetite-stimulating and appetite-suppressing
pathways altered
 Cancer Staging (1 of 2)

⬤Microscopic analysis for staging—based on

presence of metastasis
⮚ Stage I: No metastasis
⮚ Stage II: Local invasion
⮚ Stage III: Spread to regional structures
⮚ Stage IV: Distant metastasis
⬤World Health Organization’s TNM system:
⮚ T for tumor spread
⮚ N for node involvement
⮚ M for the presence of distant metastasis
Cancer Staging (2 of 2)
 Question 2

2. A patient has been diagnosed with prostate cancer

that has metastasized to the bone. The stage of this
cancer is:

A. 1
B. 2
C. 3
D. 4

Note: No input needed to proceed

 Question 2 Answer

Correct Answer: D

Cancer that has spread to distant sites, such as

a liver cancer spreading to lung or a prostate
cancer spreading to bone, is stage 4. Cancer
confined to the organ of origin is stage 1,
cancer that is locally invasive is stage 2, and
cancer that has spread to regional structures,
such as lymph nodes, is stage 3.
 Tumor Markers (1 of 2)

⬤Biochemical markers
⬤Substances produced by cancer cells that
are found on or in tumor cells, in the blood,
CSF, or urine
⮚ Hormones
⮚ Enzymes
⮚ Genes
⮚ Antigens
⮚ Antibodies
 Tumor Markers (2 of 2)

⬤Tumor markers are used to:

⮚ Screen and identify individuals at high risk for
cancer
⮚ Diagnose specific types of tumors
⮚ Observe clinical course of cancer
⬤Problem: false positives and negatives
 Classification of Tumors

⬤Classified based on immunohistochemical

analysis of protein expression
⮚ Supplemented by a more extensive genetic
analysis of the tumors
⮚ Enhanced molecular characterization subdivides
cancers into therapeutically and prognostically
relevant smaller groups
⮚ Improved treatment: personalized medicine
• Breast cancers have four types that respond to therapy
differently
 Cancer Treatment (1 of 6)

⬤Classic approaches
⮚ Surgery
⮚ Chemotherapy
⮚ Radiation therapy
⬤Immunotherapy
⬤Therapy undergoing rapid evolution
⮚ Genetic analysis of each individual’s cancer
 Cancer Treatment (2 of 6)

⬤Surgery
⮚ To prevent cancer (colon polyps)
⮚ Biopsy for diagnosis and staging
⮚ Lymph node sampling
⮚ Palliative surgery
⬤Radiation
⮚ Goals
• Eradicate cancer without excessive toxicity
• Avoid damage to normal structures
⮚ Ionizing radiation damages the cancer cell’s DNA
 Cancer Treatment (3 of 6)

⬤Chemotherapy
⮚ Takes advantage of specific vulnerabilities in
target cancer cells
⮚ Usually given in combinations designed to attack a
cancer from many different weaknesses at the
same time
⮚ Complication: death of rapidly dividing cells that
are not cancerous
 Cancer Treatment (4 of 6)

⬤Induction chemotherapy
⮚ For shrinkage or disappearance of tumors
⬤Adjuvant chemotherapy
⮚ Eliminate micrometastasis after surgery
⬤Neoadjuvant therapy
⮚ Given before localized treatment to shrink tumor
 Cancer Treatment (5 of 6)

⬤Immunotherapy
⮚ Tumor cell vaccines effective in protecting against
infective agents
⮚ Numerous potential therapeutic vaccines have
been tested with little success
⬤Immunotherapy for metastatic prostate
cancer has been approved by FDA
 Cancer Treatment (6 of 6)

⬤Targeted disruption
⮚ Used in combination with chemotherapy
⮚ Highly specific making them less toxic than
conventional chemotherapy