Neoplasia IV Cancer Pathogenesis Kristine Krafts M D

Neoplasia IV: Cancer Pathogenesis Kristine Krafts, M. D.

Neoplasia Outline • Tumor nomenclature • Tumor characteristics • Epidemiology • Cancer pathogenesis

Neoplasia Outline • Tumor nomenclature • Tumor characteristics • Epidemiology • Cancer pathogenesis • Overview • Genes • Steps • Chromosomes • Agents • Grading and staging

Neoplasia Outline • Tumor nomenclature • Tumor characteristics • Epidemiology • Cancer pathogenesis • Overview

What causes cancer?

What causes cancer? Non-lethal genetic damage.

Normal Genes Damaged in Cancer • Genes that promote growth (“proto-oncogenes”) • Genes that inhibit growth (“tumor suppressor genes”) • Genes that regulate apoptosis • Genes that repair DNA

Cancers acquire new genetic defects along the way.

Neoplasia Outline • Tumor nomenclature • Tumor characteristics • Epidemiology • Cancer pathogenesis • Overview • Genes

Characteristics of Cancer Cells • Autonomous growth • Insensitivity to growth-inhibitory signals • Evasion of apoptosis • Limitless replication • Sustained angiogenesis • Invasion and metastasis

Characteristics of Cancer Cells • Autonomous growth

Autonomous Growth • Proto-oncogene: a normal gene whose product promotes cell growth. • Oncogene: a mutated proto-oncogene. Causes tumor cell to grow autonomously. • Oncoprotein: the product of an oncogene.

Growth Signals in Normal Cells • Growth factor binds to receptor • Receptor activates signal-transducing protein • Signal-transducing protein activates 2 nd messenger • 2 nd messenger talks to nuclear transcription factors • Nuclear transcription factors start DNA transcription • Cyclins move the cell through the cycle Cell divides

Growth Signals in Cancer Cells • Growth factors may be made by cell itself • Receptor may be overexpressed • Signal-transducing protein may always be on • Nuclear transcription factors may be overexpressed • Cyclins may be overactive Cell divides on its own!

Example: RAS • RAS is a signal transduction protein • Mutated RAS is always on… • …therefore, always transducing signals… • …therefore, cell is always dividing.

Characteristics of Cancer Cells • Autonomous growth • Insensitivity to growth-inhibitory signals

Insensitivity to Growth-Inhibitory Signals • Tumor suppressor genes: normal genes whose products act like “brakes” on the cell cycle. • Mutate these guys, and you lose the brakes! • Must mutate both copies of the gene to cause tumors.

Example: RB • RB gene product stops cell at G 1 checkpoint • Mutant RB is inactive; lets cells pass through G 1! • Patients with two mutated RB genes have way, way high risk of retinoblastoma (and increased risk of other tumors).

The Cell Cycle

Patient with retinoblastoma

Orbit filled with retinoblastoma

Retinoblastoma

Retinoblastoma: characteristic “rosettes”

Another example: p 53 • Nickname for p 53: “guardian of the genome” • If a cell’s DNA is damaged, p 53 causes a pause in the cell cycle (via RB), so DNA can be repaired. • If DNA damage is irreparable, p 53 causes the cell to undergo apoptosis. • Most human tumors have p 53 mutations!

p 53 activated cell cycle arrest p 53 not activated no cell cycle arrest, no DNA repair

Characteristics of Cancer Cells • Autonomous growth • Insensitivity to growth-inhibitory signals • Evasion of apoptosis

Evasion of Apoptosis • Many proteins are involved in apoptosis: • Fas (the “death receptor”) • Executioner caspases • BCL 2 protein family • p 53 (the “guardian”) • If genes for these proteins are mutated, the call becomes immortal.

Characteristics of Cancer Cells • Autonomous growth • Insensitivity to growth-inhibitory signals • Evasion of apoptosis • Limitless replication

Limitless Replication • Normal human cells: only 60 -70 doublings • Telomeres keep getting shorter… • …leading to cell cycle arrest (via p 53 and RB). • Stem cells and cancer cells use telomerase to maintain telomere length and keep replicating.

Characteristics of Cancer Cells • Autonomous growth • Insensitivity to growth-inhibitory signals • Evasion of apoptosis • Limitless replication • Sustained angiogenesis

Sustained Angiogenesis • Tumor cells need blood too! • Can’t grow >1 -2 cm without new vessels • Tumor cells eventually learn how to stimulate angiogenesis • Lots of cytokines involved (i. e. , VEGF) • Tumor vessels are fragile and abnormal

Characteristics of Cancer Cells • Autonomous growth • Insensitivity to growth-inhibitory signals • Evasion of apoptosis • Limitless replication • Sustained angiogenesis • Invasion and metastasis

Invasion and Metastasis • To invade, tumor cells must: • Loosen contacts between cells • Degrade extracellular matrix • Migrate away from the original site • Some tumors lodge in nearest capillary bed • Some tumors show tropism

clonal growth metastatic subclone intravasation tumor cell embolus extravasation

Tumor cells surrounding and invading vessel

Tumor cells now within vessel

How do all these genetic mutations arise? • We are constantly exposed to mutagenic agents. • But we don’t get many cancers because normal cells are able to repair DNA damage. • Many systems for DNA repair exist. • If you inherit a defect in any of these systems, you’ll be more likely to get cancer.

Number of cell divisions/day 11 10 Spontaneous mutation rate 10 -6 Number of mutations/day 5 10

Neoplasia Outline • Tumor nomenclature • Tumor characteristics • Epidemiology • Cancer pathogenesis • Overview • Genes • Steps

Steps to Cancer • Every tumor results from the accumulation of a bunch of mutations • Average: 90! • Normally, body fixes or gets rid of mutated cells (using RB, p 53) • For a tumor cell to grow, one of its mutations must be within these checkpoint/guardian genes.

Neoplasia Outline • Tumor nomenclature • Tumor characteristics • Epidemiology • Cancer pathogenesis • Overview • Genes • Steps • Chromosomes

Chromosomal Changes • Genetic damage can be subtle, invisible on a karyotype (point mutation) • …or obvious, visible on a karyotype • Some karyotypic abnormalities occur predictably in certain tumors (leukemias, lymphomas, solid tumors)

Chromosome banding

prophase metaphase anaphase

metaphase spread

Normal male karyotype

Balanced Translocations • Common! • Either put a proto-oncogene next to a promoter… • …or create a fusion gene that makes a bad, growth-promoting product • Most common in hematopoietic tumors • Example: Philadelphia chromosome

Deletions • Deletion of part or all of a chromosome • Usually, deletion of a tumor suppressor gene • Most common in solid tumors • Example: del 13 q 14 in retinoblastoma

Neoplasia Outline • Tumor nomenclature • Tumor characteristics • Epidemiology • Cancer pathogenesis • Overview • Genes • Steps • Chromosomes • Agents

Carcinogenic Agents • Chemicals • Radiation • Bugs/viruses

Chemicals • Direct-acting agents, e. g. , chemotherapy drugs • Indirect-acting agents (require conversion to become carcinogenic), e. g. , hydrocarbons, aflatoxin B, nitrites • Mechanism: electrophile groups bind to DNA

Radiation Ionizing radiation • Causes chromosome breakage, translocations • Examples: miners (lung cancer), atomic bomb radiation (leukemia), therapeutic head/neck radiation (thyroid cancer) UV light • Causes formation of pyrimidine dimers • Repair pathways usually fix – but can become overwhelmed • Examples: squamous cell carcinoma, melanoma

normal DNA with pyrimidine dimers

Bugs • HTLV-1: T-cell lymphoma • HPV: Cervical cancer • EBV: various lymphomas • HBV and HCV: hepatocellular carcinoma • H. pylori: gastric cancer, lymphoma

Neoplasia Outline • Tumor nomenclature • Tumor characteristics • Epidemiology • Cancer pathogenesis • Overview • Genes • Steps • Chromosomes • Agents • Grading and staging

Grading and Staging • Used for malignant tumors • Helps determine treatment and prognosis • Grading • Tells you how nasty the tumor looks (use microscope) • Somewhat useful • Staging • Tells you how far the tumor has spread (use imaging) • Very useful

Grading system for breast cancer Tubules lots of tubules some tubules rare tubules Pleomorphism 1 2 3 small, uniform cells larger, less uniform cells markedly pleomorphic cells Mitoses 1 2 3 0 -9 mitoses/10 hpf 10 -19 mitoses/10 hpf ≥ 20 mitoses/10 hpf add all points together Grade Low grade Intermediate grade High grade Score 3 -5 6 -7 8 -9 5 y survival >95% 80% 60% 1 2 3

Breast carcinoma low grade

Breast carcinoma high grade

TNM staging system for non-small cell lung cancer T=Tumor Tis – in situ tumor T 1 – small tumor T 2 – larger tumor T 3 – larger or invasive tumor T 4 – very large/very invasive N=Nodes N 0 – no lymph node involvement N 1 – a few regional nodes N 2 – lots of regional nodes N 3 – distant nodes M=Metastases M 0 – no metastases M 1 – metastases

TNM staging system for non-small cell lung cancer Overall stage T N M Treatment 5 y prognosis Stage 0 Tis N 0 M 0 Surgery only 75% Stage I T 1 or T 2 N 0 M 0 Surgery ± radiation 50% Stage II T 1 T 2 T 3 N 1 N 0 M 0 M 0 Surgery and radiation ± chemotherapy 30% M 0 M 0 Chemotherapy ± radiation to debulk Maybe surgery 10% M 1 Palliative care Maybe chemo or radiation <2% Stage III Stage IV T 1 or T 2 N 2 T 3 N 1 or N 2 Any T N 3 T 4 Any N Any T Any N

Grading and Staging Grading = microscopic Staging = clinical Staging is more useful.