VMED 02610: Pathobiology I General Pathology – Neoplasia Lecture 2

A malignant tumor of the liver is called:

Hepatocellular carcinoma

Neoplasms develop as the result of

multiple genetic and epigenetic changes that occur over a relatively long time course

What are the three steps of tumor development

1. initiation

2. promotion

3. progression

What is the defintion of INITIATION this is the first step of tumor development

Introduction of an irreversible genetic change into

normal cells by the action of a mutagenic initiating agent (initiator)

What does INITATOR mean, this is the second development of tumors

Chemical or physical carcinogen that damages DNA

How do initiated cells look like

May appear morphologically normal and may remain quiescent for years

Do initiated cells have a growth advantage ?

May have a growth advantage that allows them to respond more vigorously to growth signals or are more resistant to apoptotic signals

Do initiated have a fixed permanent mutation

yes they do

These initiated cells are the substrate for

promotion

What does promotion mean

when we have an Outgrowth of initiated cells in response to selective stimuli, which are typically promoters or promoting agents

What drives promotion in tumor development

Drives proliferation of initiated cells

What do promotoes create?

Creates a proliferative environment in which initiated cells gain a growth advantage

Are promotors from the tumor development are reversible?

Promotor effects are usually reversible

Removing the promoting stimulus can halt what in the promotor tumor development

progression

What are examples of promotors

estrogen, testosterone, UV radiation, chronic inflammation, bacterial/viral infections

What does progression mean in tumor development

Involves genetic and epigenetic changes in tumor cells and their environment which select for increasingly malignant clones of cells

What does progression tumoe development conver to

Converts a benign tumor into an increasingly malignant tumor and eventually into a metastatic tumor

Under initiation of tumor development is it genetically reversible or irrversible

genetic

irreversible

Under promotion of tumor development is it genetically reversible or irrversible

nongentic

reversible

Under progression of tumor development is it genetically reversible or irrversible

genetic/nongenetic

irrversible

Put in order of progression of tumor development: benign → malignant → metastasis

1. benign

2. malignant

3. irreversible

Initiator must be administered before what

promotor for tumor growth

What are the factors that can affect intrinsic factors

• By-products of normal metabolism in the cell

• Copying errors during replication

• Chromosomal abnormalities arising from decreased telomere length altered telomerase activity, and mistakes in chromosome

segregation

• Occur in every dividing cell and can result in mutation without any external exposure

What are the factors that affect extrinsic factors

• Chemical, environmental, and viral agents that interact with DNA to cause cancer

• Preventable or avoidable

• Mutagen – agent that creates DNA damage

• Carcinogens – agents that cause cancer by any mechanism

What are examples of extrinsic factors; chemicals

• Ptaquiloside (bracken fern) → Urothelial carcinoma in cattle

• Tobacco smoke → Neoplasia in the nasal cavity and

  respiratory tract in dogs

• Asbestos → Canine mesothelioma

Radiation carcinogens are able to do what

initiate and promote tumorigenesis

What are examples of radiation extrinsic factors

• Cutaneous squamous cell carcinoma (SCC)

• Cutaneous hemangioma/hemangiosarcoma

The classification is retrovirus what are some virus examples

• Avian sarcoma-leukosis virus complex

• Feline leukemia virus (FeLV)

• Bovine leukemia virus

• Feline immunodeficiency virus

• Maedi-Visna virus

We mentioned the examples of retrovirus

• Avian sarcoma-leukosis virus complex

• Feline leukemia virus (FeLV)

• Bovine leukemia virus

• Feline immunodeficiency virus

What animals are affected

• fowl (bird)

• cat

• cattle

• cat

• Sheep

What is an example of Papovavirus

Papillomavirus

Papillomavirus affects what species

various

The classficiation is herpesvirus what is an example

Gallid herpesvirus 2 (Marek's disease)

What animal is affected by Gallid herpesvirus 2 (Marek's disease)

Fowl

The virus classification is poxvirus what is an example

various

poxvirus affects what

various

we mentioned that the retroviruses examples are Avian sarcoma-leukosis virus complex and it affects fowls what are the associated tumors

Sarcomas, carcinomas, lymphomas, leukemia

FELV, bovine leukemia virus, and FIV are retrovirus what are the associated tumors (we already know what animals affects them)

Leukemias, lymphomas

Maedi vsina virus affects sheep but what is their tumor association affects

pulmonary carcinomas

We know papillomavirus affects various species but what are the associated tumors

papillomas/carcinomas

We know that Gallid herpesvirus 2 affects fowls what are the assocaited tumors

lymphoproliferative disease

We know pxvirus have various viruses and affect various species but what are the associated tumors

fibromas or papillomas

Tumor Suppressor Genes are the genes that control what

control cell cycle, apoptosis, DNA repair, and other pathways

Tumor Suppressor Genes Prevent or suppress what

cancer when they are in their active form

Tumor Suppressor Genes Act as “brakes” on what

proliferation

Loss of tumor suppressor genes is frequently found in

neoplastic cells

What is the two hit hypothesis

Both alleles of a tumor suppressor gene must be inactivated to eliminate its activity

What is the first “hit” of the two hit hypothesis

• germline mutation affecting every cell in the body

• Common in hereditary cancer syndrome and present from birth

What is the second “hit” of the two hit hypothesis

• – loss of the remaining normal allele in single somatic cells

• Lost of heterozygosity

What does Sporadic (nonhereditary) cancers mean

Both hits must occur by chance within the same cell

What is the purpose of p53

Plays a critical role in cell-cycle arrest and the induction of apoptosis after DNA damage

p53 is inactivated in many

many cancers

DNA damage goes unrepaired, the cell proceeds through what

division, and genetic changes become fixed in the genome

What are the retinoblastoma gene prevent

Prevents excessive cell growth by inhibiting cell cycle progression until a cell is ready to divide

retinoblastoma gene is inactived in what

Inactivated in many cancers

What does retinoblastoma gene allows cells to do do what

Allows cells to progress through the cell cycle inappropriately

What are proto-oncogenes

Normal cellular genes that regulate cell growth and differentiation

What do proto-oncoenes encode what

Often encode products such as growth factors and their receptors, cell cycle regulators, DNA-binding proteins, transcription factors, etc.

Can proto-oncogenes be a problem?

Can become a problem once activated inappropriately

What are oncogenes

Result when proto-oncogenes are activated by overexpression or mutation

Oncogenes drive what

Drives proliferation and render the cell unresponsive to normal growth inhibitory signals

Oncogene activation is typically dominant or recessive

dominant

• due to a single activated allele can be enough to contribute to transformation

What are the parts of activation of proto-oncogenes

1. amplication

2. mutation

3. overproduction

What does amplificaiotn mean in activation of proto-oncogenes

Signal to transcribe the gene results in the production of many more copies of mRNA than usual, because the gene itself is present in extra copies

What does mutation mean in activation of proto-oncogenes

• Constitutive activation of the encoded protein

• Protein is permanently ‘turned on’ and unresponsive to normal inhibitory signals

What does overproduction mean in activation of proto-oncogenes

• Neoplastic cells acquire the ability to synthesize the same growth factors to which they are normally responsive, creating a self-sustaining autocrine loop of activation

What are oncoproteins

• Protein encoded by an oncogene that drives increased cell proliferation

• Ability to promote cell growth in the absence of normal growth-promoting signals

What is the purpose of metastasis

Establishment of colonies of tumor cells at distant sites from the

primary tumor

What is the most reliable hallmark of malignancy

Most reliable hallmark of malignancy

Death is usually due to

due to tumor metastasis and interference with critical bodily functions

What is the first step of mechanism of tumor invasion and metastasis of a tumor

adhesion

What is the second step of mechanism of tumor invasion and metastasis of a tumor

migration

What is the third step of mechanism of tumor invasion and metastasis of a tumor

stromal invasion

What is the fourth step of mechanism of tumor invasion and metastasis of a tumor

epithelial mesenchymal transition

What is the fifth step of mechanism of tumor invasion and metastasis of a tumor

intravasation

What is the sixth step of mechanism of tumor invasion and metastasis of a tumor

tumor emboli

What is the seventh step of mechanism of tumor invasion and metastasis of a tumor

extravasation

What is the defintion of adhesion

Tumor cells must detach from the main tumor mass, penetrate the basement membrane, and enter the extracellular matrix (ECM)

Intercellular adhesion structures must be what

dismantled

What does migration mean in tumor metastasis

Mediated by alteration in the cytoskeleton and the cellular adhesion structures

Migration is stimulated by (in tumor metastasis)

Stimulated by autocrine growth factors produced by the tumor cells

What is stromal invasion

Neoplastic epithelial cells actively degrade basement membrane and ECM components by increasing net protease activity

What is does stromal invasion penetrate where

Penetrate basement membrane and invade surrounding tissue

Stromal invastion: the enzyme Proteases may be produced and activated by

tumor cells or tumor cells may induce nonneoplastic stromal

cells to produce these enzymes

Epithelial Mesenchymal transition are carcinomas ?

Some carcinomas undergo this transition

How do we describe epithelial mesenchymal transition

Characterized by loss of intercellular adhesion structures, enhanced expression of proteases, acquisition of migratory capabilities, reduced expression of epithelial cytokeratins, and de novo expression of vimentin (mesenchymal marker)

What do epithelial mesenchymal transition allow

Allows neoplastic epithelial cells to dissociate and migrate, thus fostering local invasion and distant metastasis

What do we mean by intravasation, what do they do

Neoplastic cells invade blood or lymphatic vessels by penetrating endothelial basement membranes and passing between or through endothelial cells

Intravasation are attracted to what

Attracted to vessels by chemotactic factors

Intravasation are facilitated by what

Facilitated by tumor-associated macrophages

What are tumor emboli in tumor metastasis

Tumor cells clump together to form emboli within the vessels

Tumor cells may be

recognized and attacked by host lymphocytes or shielded from immune attack by surrounding platelets

What is extravastion

Intravascular tumor cells leave vessels

Where do extravasation attach to

Tumor cells attach to the vascular endothelium, pass between or through the endothelial cells, and penetrate the basement membrane to enter the ECM

Where is the site of extravasation

Site at which tumor cells exit the vessels is determined by the ability of the tumor cells to interact with adhesion molecules on endothelial cells

Metastatic site must provide what

suitable microenvironment

Some ____ preferentially metastasize to specific sites

neoplasms

What are the pathways of tumor metastasis

• Lymphatic spread

• Hematogenous spread

• Transcoelomic spread

What is lymphatic spread

• Most carcinomas metastasize via the lymphatic system

• Regionally lymph nodes are usually affected first

What is hematogenous spread

• Most sarcomas metastasize via the blood vessels

• Generally invade thin-walled veins rather than arteries