Tumor dissemination, genetics of cancer, prognosis - Exam 4

Tumor dissemination

Spread of tumor from one location to another

What are the six steps of tumor dissemination?

1. Adhesion

2. Migration

3. Stromal invasion

4. Intravasation

5. Tumor emboli

6. Extravasation

Adhesion

Intracellular adhesion structures dismantled giving tumors a higher affinity towards ECM

Migration

Alterations in cytoskeleton and cellular adhesion structures allow tumor to move through ECM

Stromal invasion

Tumor penetrates basement membrane to invade surrounding tissues

Intravasation

Cancer cells invade blood or lymphatic vessels

Tumor emboli

-Tumor cells clump together to form a small emboli once they are inside a vessel

-Can be protected by platelets

Extravasation

Tumor cells leaving vessels to set up a new metastatic site

What are four ways that cancer can spread?

1. Lymphatic

2. Hematogenous

3. Transcoelomic

4. Transmissible

What types of cancer usually spread lymphatically?

-Most carcinomas

-Some sarcomas

Lymphatic spread

-Same as vascular system

-Lymph nodes closest to tumor are affected first

What types of cancer usually have a hematogenous spread?

Sarcomas

Hematogenous spread

-Tumors invade veins then arteries

-Usually spread to liver and lungs

Transcoelomic spread

-Tumors on abdominal surfaces

-Usually confined to a cavity but spread quickly

Carcinomatosis

Multiple tumor masses throughout the abdomen

Transmissible tumors

Physical tumor is spread between animals in the same species

What are two examples of transmissible tumors?

-Devil facial tumor disease (DFTD) of Tasmanian devils

-Canine transmissible venereal tumor (STD)

How does cancer occur?

Accumulation of genetic and epigenetic abnormalities

What are six types of DNA mutations?

1. Point mutations

2. DNA strand breaks

3. Insertions and deletions

4. Amplifications

5. Aneuploidy

6. Chromosomal instability

Point mutations

Altering gene product or level of expression

DNA strand breaks

Cause gene alterations

Insertions and deletions

Change in a single base pair can alter gene products

Amplifications

More than one copy of a gene is present

Aneuploidy

Abnormal number of chromosomes

Chromosomal instability

Two pieces of chromosome arms break off and reattach inappropriately

Germline mutations

-Sex cells

-Transmitted to offspring (heritable)

Cancer syndrome

Families with germline mutations that result in the development of a specific tumor

Somatic mutations

-Body cells

-Sporadically acquired and cannot be transmitted to offspring

-Accumulate over time

Epigenetic

Heritable change in gene expression that is not from a DNA mutation

What are two examples of epigenetic changes?

-DNA methylation

-Histone modification

DNA methylation

-Methyl group added

-Turns genes off

Histone modification via acetylation

-Acetylation results in a more relaxed chromatin configuration

-Turns genes on

What genes are molecular determinants of cancer?

-Tumor suppressor genes

-Oncogenes

Proto-oncogenes

Normal cellular genes that regulate cell growth and differentiation

Oncogenes

-Overexpressed or mutated proto-oncogenes

-Drive proliferation and “turn on” cancer

Mutated RAS

-Cannot be inactivated and continue cell cycle progression

-Leads to a constant cell division signal

Tumor suppressor genes

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

What does an inactivated tumor suppressor gene lead to?

Uncontrolled cell proliferation and tumor growth

Two-hit hypothesis

Both alleles of a tumor suppressor gene must undergo mutation for cancer to develop

Haploinsufficiency

-Inactivation of one copy can lead to tumor growth

-p53

Multistage carcinogenesis

-Orderly morphologic progression of a normal cell to cancerous cell

-Initiated by a loss of mutation

What are two mechanisms of carcinogenesis?

-Intrinsic factors

-Extrinsic factors

Intrinsic factors

DNA-damaging metabolites produced as a by-product of ordinary cell metabolism (ex. ROS)

Extrinsic factors

-Interact with DNA to cause cancer

-Termed mutagens or carcinogens

Mutagens

Agents that mutate DNA

Carcinogens

Agents that cause cancer

What are some examples of carcinogens?

-Chemicals

-Radiation

-Viruses

Direct-acting chemical carcinogens

Carcinogenic as they enter the body

Indirect-acting carcinogens

Carcinogenic only when they are processed by the liver

Radiation

-Complete carcinogens

-Able to initiate and promote tumor growth

-Direct DNA damage

Oncogenic viruses

Get into DNA and mutate it

What is prognosis determined by?

-Tumor type

-Grade

-Stage

-Completeness of excision

Histopathologic diagnosis

-Cells scrutinized for features of malignancy

-Can obtain a definitive diagnosis

How are grades evaluated?

-Pathologist

-Evaluate degree of differentiation

What are three degrees of differentiation within grades?

-Well differentiated (Grade I)

-Moderately differentiated (grade II)

-Poorly differentiate (grade III)

How are tumor stages evaluated

-Clinicians

-Extent of tumor growth

TNM system

T - size of primary tumor

N - degree of lymph node involvement

M - extent of metastasis

-Graded on a scale of 0-IV

Stage 0

Carcinoma in situ

Stage I

Invade a little into tissue of organs

Stage II

Invaded extensively into tissue

Stage III

Invade completely into tissues

Stage IV

Extensive metastasis throughout body