Neoplasia (COMPLETE SET)

What can vary cancer incidences?

Geography

Age

Race

Genetic background

What is tumorigenesis?

Multi-step process by which normal, healthy cells transform into cancerous, tumor-forming cells

After exposure of cell to mutagen/initiator → Enhanced by exposure to a promoter → Proliferation of mutated cells

What are some examples of environmental and lifestyle factors implicated in carcinogenesis?

Infectious agents

Smoking

Alcohol

Diet

Obesity

Reproductive history

Exposure to environmental carcinogens

What cellular factors increase the risk of cancer?

Reparative proliferation caused by:

• Chronic inflammation

• Tissue injury

• Certain forms of hyperplasia

• Immunodeficiency

What are two important determinants of cancer risk?

Environmental factors

Genetic factors

What is neoplasia?

A disorder of cell growth that is triggered by a series of acquired mutations affecting a single cell and its clonal progeny

• Cells replicate incessantly because of resistance to growth regulation

What is a neoplasm?

An abnormal mass of tissue whose growth exceeds and is uncoordinated with normal tissues

• Initially means swelling caused by inflammation, now is interchangeable with tumor

What are the two major components of a tumor?

Parenchyma (neoplastic cells)

Stroma (supportive connective tissue, blood vessels, inflammatory cells)

What categories a benign tumor?

Localized

Usually slow-growing

Well-differentiated

No metastasis

Not always harmless

What categories a malignant tumor?

Invasive

Faster growth

Poorly differentiated/anaplastic

Can metastasize

Not always fatal

What are the two hallmarks that definitively distinguish malignant tumors from benign tumors?

Local invasion

Metastasis

What is differentiation?

The extent to which neoplastic cells resemble their cells of origin, both morphologically and functionally

What is anaplasia?

Lack of differentiation

A hallmark of malignancy

Which tumor type generally has a higher mitotic index?

Malignant tumors

What is cellular pleomorphism?

Cells varying in size and shape

What is nuclear pleomorphism?

The nuclei are disproportionally large

Nuclear shape is variable and irregular

Hyperchromatic

What morphologic changes are often associated with anaplasia?

Cellular pleomorphism

Nuclear pleomorphism

Tumor giant cells

Atypical mitoses

Loss of polarity

What are tumor giant cells?

Large cells with enormous nucleus or multiple nuclei

What is atypical mitoses?

High mitotic index

Atypical and bizarre mitotic features (tripolar spindle)

What is hyperchromasia?

Darkly staining nuclei caused by increased DNA content

What nucleus-to-cytoplasm ratio is characteristic of malignant cells?

Approximately 1:1

What nucleus-to-cytoplasm ratio is characteristic of normal cells?

Approximately:

• 1:4

• 1:6

Why are atypical mitoses important?

They are strong evidence of malignancy

What does loss of polarity mean?

Tumor cells no longer maintain their normal architectural orientation

If a tumor is surrounded by a fibrous capsule and sharply separated from surrounding tissue, is it more likely benign or malignant?

Benign

If tumor cells penetrate through the basement membrane into surrounding tissue, is the tumor benign or malignant?

Malignant

Approximately what percentage of cancer deaths result from metastasis?

About 90%

What is a carcinoma?

Malignant tumor arising from epithelial tissue

Accounts for 80–90% of cancers

What is an adenocarcinoma?

Malignant tumor arising from glandular epithelium

What is squamous cell carcinoma?

Malignant tumor arising from squamous epithelium

What is a sarcoma?

Malignant tumor arising from mesenchymal tissues derived from mesoderm

What are some examples of tissues that sarcoma can originate from?

Bone

Muscle

Fat

Cartilage

What is myeloma?

Cancer that originates in the plasma cells of the bone marrow

What is leukemia?

Cancer of the bone marrow

Often associated with overproduction of immature white blood cells

What is lymphoma?

Cancers developed in the glands or nodes of the lymphatic system

What does it mean when a cancer is classified as mixed type?

More than one cell type

Ex. Carcinosarcoma

What is a benign tumor of fat?

Lipoma

What is a malignant tumor of fat?

Liposarcoma

What is a benign smooth muscle tumor?

Leiomyoma

What is a malignant smooth muscle tumor?

Leiomyosarcoma

What is a benign glandular epithelial tumor?

Adenoma

What is a malignant glandular epithelial tumor?

Adenocarcinoma

What is a benign blood vessel tumor?

Hemangioma

What is a malignant blood vessel tumor?

Angiosarcoma

What were the eight major hallmarks of cancer that were discussed?

Sustained proliferative signaling

Evading growth suppressors

Evading cell death

Replicative immortality

Angiogenesis

Invasion/metastasis

Immune evasion

Metabolic reprogramming

What is the most frequently mutated oncogene in human cancer?

RAS (Rat Sarcoma Virus)

What activates RAS?

Guanine Exchange Factors

• Facilitates RAS binding to GTP and inactivated by intrinsic GTPase activity

What type of protein is RAS?

Membrane-associated small GTP-binding protein

What are the three isoforms of RAS?

H-RAS

K-RAS

N-RAS

What is the active form of RAS?

RAS-GTP

What is the inactive form of RAS?

RAS-GDP

Which are the two key pathways for proliferation in RAS?

PI3K-AKT pathway

RAF-MAPK pathway

Which cancer has RAS mutations in approximately 90% of cases?

Pancreatic adenocarcinoma and cholangiocar-cinomas

Which mutation occurs in about 40% of melanoma?

BRAF mutation

What is the most mutated oncogene in humans?

RAS

What receptor is amplified in many breast cancers?

HER2/neu (EGFR family)

What leukemia is caused by the BCR-ABL translocation?

Chronic myelogenous leukemia (CML)

What does PTEN normally do?

Regulates the PI3K-AKT pathway

• Negative-feedback

Loss of PTEN causes activation of which pathway?

PI3K-AKT signaling

What are examples of hallmark 1: self-sufficiency in growth signals?

Growth factors are secreted by cancer or stromal cells

Overexpression or mutation of GF receptors

Downstream signaling pathway mutations

Disruptions of negative-feedback mechanisms

Dysregulated cell cycle control

What are the two canonical growth suppressors?

RB

p53

What was the first tumor suppressor gene discovered?

RB

What cell-cycle checkpoint is controlled by RB?

G1 → S checkpoint

What does RB stand for?

Retinoblastoma

What does RB integrate from extracellular and intracellular sources?

Pro- and anti-proliferative signals

RB is lost in what two types of cancer?

>70% of osteosarcomas

~90% of SCLC

How is RB inactivated in human cancers?

Loss-of-function mutations

Amplifications of cyclin D and CDK4 genes

Loss of CDK inhibitors such as p16

Viral proteins that bind and inhibit RB (HPV E7)

What virus produces E7 protein that inhibits RB?

HPV

What is the "guardian of the genome"?

TP53

What is the most commonly mutated gene in human cancer (>50%)?

TP53

What functions does p53 perform?

Cell cycle arrest

DNA repair

Senescence

Apoptosis

What protein normally degrades p53?

MDM2

What activates p53 following DNA damage?

ATM pathway

• dsDNA breaks

How is p53 inactivated in human cancers?

Biallelic loss-of-function mutations

Overexpression of MDM2 and related proteins

Viral oncoprotein inactivation (HPV E6)

What is the most common mechanism cancer cells use to evade apoptosis?

Loss of p53 function

Which anti-apoptotic protein is classically overexpressed in cancers?

BCL2

What are BAX and BAK?

Pro-apoptotic proteins

What does APAF-1 stand for?

Apoptotic Protease Activating Factor-1

What are the four mechanisms cancer cells use to evade apoptosis?

Loss of p53 function

Overexpressing anti-apoptotic members of the BCL2 family

Loss of APAF-1

Upregulation of IAP

What are telomeres?

Repetitive DNA sequences at chromosome ends

What enzyme allows cancer cells to become immortal?

Telomerase

What happens when telomeres become critically short?

Cells undergo senescence or apoptosis

What are two outcomes of incorrect new double-stranded breaks?

Mitotic catastrophe (death)

Telomerase reactivation (cancer)

Why do tumors need angiogenesis?

To obtain oxygen and nutrients

• Lacking in solid tumors

What is the most important angiogenic factor?

VEGF

What transcription factor responds to hypoxia?

HIF-1α

What tumor suppressor promotes degradation of HIF-1α?

VHL

What triggers the angiogenic switch?

Disruption of the balance between pro-angiogenic and anti-angiogenic factors

Allows the tumor to progress from a non-angiogenic to an angiogenic phenotype

When can an angiogenic switch occur?

During tumor progression

• Premalignant to malignant

• Micrometastasis to metastasis

• Recurrence

What is a hypoxia-inducible factor 1α?

Transcription factor and a master regulator of:

• Hypoxia signaling

• Regulating expression of angiogenic factors

  • Ex. VEGF

What happens to hypoxia-inducible factor 1α during normoxia?

HIF-1α is hydroxylated and recognized by:

• von Hippel-Lindau (VHL)

  • An ubiquitin E3 ligase (like MDM2)

Can cause HIF degradation

What is a major angiogenic factor?

VEGF

What are the properties of VEGFs?

Capillary and lymph duct formation

Monocyte migration

Hematopoiesis

Recruitment of hematopoietic progenitor cells from the bone marrow

Regulation of the endothelial cell pool during development

Capillary permeability

What do cancers recruit to stimulate angiogensis?

Macrophages

What is metastasis?

The spread of a tumor to sites that are physically discontinuous with the primary tumor

What process allows epithelial cancer cells to become migratory?

Epithelial-Mesenchymal Transition (EMT)

What process allows metastatic cells to establish new tumors?

Mesenchymal-Epithelial Transition (MET)

What imaging study detects increased glucose metabolism?

PET scan using FDG

FDG uptake (which highlights aerobic glycolysis) demonstrates what metabolic phenomenon?

Warburg effect

Which organs are common metastatic targets?

Bone

Liver

Lung