PATHO Ch. 12 Cancer Biology

the term Cancer derives from

the greek word for crab, " karkinoma"

second leading cause of death

cancer

tumor

mass of rapidly dividing cells that can damage surrounding tissue

neoplasm

new growth

are all tumors cancerous? T/F

False

malignant tumor

A cancerous tumor that is invasive enough to impair the functions of one or more organs.

benign growth

non-cancerous, non-invasive growth

lipoma

benign fatty tumor

cancer

diseases in which abnormal cells divide without control and are able to invade other tissues

Benign tumor characteristics

• Well-differentiated

• Usually slow to divide

• Encapsulated---does not invade surrounding area

• Does not spread by metastasis

* suffix -oma (lipOMA)

-oma

tumor, mass

benign tumors of the colon

polyps

you learn that an individual has benign tumors. what does this mean? the tumors:

are encapsulated

malignant tumor characteristics

- Grow rapidly

- Not encapsulated

- Invasive

- Poorly differentiated

- High mitotic index

- Stroma

* Can spread distantly (metastasis)

anaplasia

microscopic hallmark of cancer

loss of cellular differentiation

pleomorphic

composed of a variety of types of cells (mixed-cell tumors)

nucleus of malignant cells

large darkly stained nuclei

metastasis

The spread of cancer cells beyond their original site

cancers are named by

the cell type they originate from

carcinomas

cancers that arise in the epithelial tissues (skin)

adenocarcinomas

cancers of glandular epithelial cells (breast glandular tissue)

sarcoma

malignant tumor of connective tissue (muscle, bone, connective tissues)

lymphomas

cancer of the lymphatic tissues

leukemias

cancers of the blood

hodgkin disease and ewing sarcoma are named for

historical reasons

carcinoma in situ (CIS)

Preinvasive epithelial malignant tumors of glandular or epithelial origin that have not broken through the basement membrane or invaded the surrounding stroma

carcinoma in situ occurs in

cervix

skin

oral cavity

esophagus

bronchus

in glandular epithelium, in situ occurs in

stomach, breast, endometrium, large bowel

3 fates of in situ (CIS) lesions

1- remain stable for long time

2- progress to invasive cancers

3- regress and disappear

10 hallmarks of cancer

1. sustaining proliferative signaling

2. evading growth suppressors

3. avoiding immune destruction

4. enabling replicative immortality

5. tumor-promoting inflammation

6. activating invasion and metastasis

7. inducing angiogenesis

8. genome instability and mutation

9. resisting cell death

10. deregulating cellular energetics

microenvironment of a cancerous tumor

heterogenous mixture of cells both cancerous and benign

cancer is a disease of

aging

Age and Cancer Incidence

as you age, the immune system begins to decline therefor allowing more things to slip past and potentially cause cancers.

mutational genetic changes

alteration in the DNA sequence affecting expression or function of a gene

-mutations (point, insertion, deletion, driver, passenger)

-chromosome translocation

-gene amplification

-clonal proliferation

chromosome translocation

large change where a piece on one chromosome is transferred to another

- Philadelphia chromosome

- chronic myelogenous leukemia

9q34.1 (ABL)

signaling protein

gene amplification

result of repeated duplication of a region of a chromosome

- instead of 2 copies of a gene there are tens of hundreds of copies present.

- seen in neuroblastoma

point mutations

changes in a single nucleotide pair of a gene

driver mutations

drive the progression of cancer

- 140 different types

involves:

- activation of proto-oncogenes

- inactivation/loss of tumor suppressor genes

- mutation resulting in overexpression of products that promote proliferation or prevent apoptosis

passenger mutations

have no direct contribution to cancer phenotype

random events

insertion mutations

occur when a segment of DNA is moved from one chromosome to another

deletion mutations

Part of a gene sequence is missing-causes a frameshift mutation

silent mutation

A mutation that changes a single nucleotide, but does not change the amino acid created.

missense mutation

A base-pair substitution that results in a codon that codes for a different amino acid.

nonsense mutation

changes a normal codon into a stop codon

wild type

most prevalent form of gene

NORMAL

after a large amount of driver mutations occur..

cell becomes cancerous

clonal proliferation

The expansion of a specific cell linage through repeated rounds of mitosis originating from a single cell.

- mutated clones multiply rapidly

malignant transformation

the process during which a normal cell becomes a cancer cell

cellular genes may become cancerous oncogenes due to

1. point mutations (ras)

2. amplification (n-myc)

3. chromosomal translocation (c-myc in burkett lymphoma)

proto-oncogenes

code for proteins that stimulate NORMAL cell growth and division

oncogenes

genes that cause cancer by blocking the normal controls on cell reproduction

tumor suppressor genes

encode proteins that help prevent uncontrolled cell growth

- do not allow cell cycle to progress

- ex: Rb, p53

p53

This tumor suppressor gene causes cell cycle arrest in G1, providing time for DNA repair.

it is a caretaker gene "guardian of the genome"

If repair is successful, cells re-enter the cycle.

If unsuccessful, apoptosis.

Myc protein

A transcription factor involved in regulation of cell division.

Mutated p53 protein

cell cycle continues UNCHECKED

leading to mutations and uncontrolled proliferation (cancer)

Ras protein

a G protein that relays a signal from a growth factor receptor on the plasma membrane to a cascade of protein kinases

mutated Ras

cell goes into autocrine mode to stimulate its own activation and allows for uncontrolled proliferation

autocrine

a chemical signal that binds to and affects the cell that makes it

tumor stroma

Supportive tissue surrounding tumor cells.

clonal proliferation chart

look at pic

epigenetic effects on gene instability

DNA methylation

altered expression of non-coding RNA (miRNA/miR)

modulation of gene

chromosome instability (loss of tumor suppressing gene)

caretaker genes

encode for proteins that are involved in repairing damaged DNA

ex: errors in DNA replication

accumulation of mutations results in

malignant transformation

chromosome instability leading to the development of cancer may result in the overexpression of

oncogenes

body cells can only divide

about 120 times (hayflick limit)

this is why we can only live to about 100 years old.

Hayflick limit

the maximum number of times a cell can divide before dying

telomeres

protective caps on the end of chromosomes maintained by telomerase

- become SMALLER with each cell division

- cancer cells can activate telomerase leading to continued division

telomerase

controls the lengthening of telomeres

unlimited divisions lead to cancer.

angiogenesis

formation of new blood vessels into the tumor to supply it with nutrients.

VEGF (vascular endothelial growth factor)

stimulates growth of new blood vessels

bFGF (basic fibroblast growth factor)

progenitor to neuroblast

cancer cells use _____________ glycolysis and _____________

anaerobic glycolysis and fermentation

The Warburg Effect and Cancer

- many cancer cells produce ATP through increased glycolysis followed by lactate production

- Cancer cells: aerobic glycolysis is used to rapidly produce ATP and is termed the Warburg Effect

- causes rapid cell growth

reverse warburg effect

Some tumors use oxidative stress as a weapon to extract recycled nutrients from cancer-associated fibroblasts in stromal tissue

used to generate large amounts of AT

chronic inflammation can lead to

cancer due to active inflammatory response

- which stimulates wound healing response (proliferation)

- angiogenesis

ex: h. pylori increases risk of stomach cancer

TAM (tumor associated macrophage)

key cells that promote tumor survival

secrete substances like chemokines to promote metastasis

support inflammation to allow cancer to thrive

tumor associated antigens

Cancer cells may display altered cell surface antigens as a result of malignant transformation. Immunologic surveillance is the response of the immune system to these antigens.

if a cancer cell can mask a tumor associated antigen, it can...

get the immune system or Tc cells to not recognize it and allow it to invade.

tumor cells display abnormal or overexpressed...

tumor associated antigens on their surface using MHC class 1 molecules.

cancer cells are usually destroyed by

cytotoxic T cells (Tc cells)

NK cells

NK cell mediated killing happens with cells that have..

altered glycoproteins (on CD1 or MHC III) and glycolipids (on surface of cancer cells)

immune surveillance hypothesis

predicts developing malignancies are suppressed by efficient immune response

tumor cells can suppress NK cells by

presenting altered glycoproteins

some tumors secrete IL-10 which suppress NK function

antitumor immunity

immune system's ability to recognize, target, and eliminate cancer cells.

T cell recognition of tumor antigen leading to T cell activation

failure to produce tumor antigen leads to

lack of T cell recognition of tumor

mutations in MHC genes or antigen processing genes leads to

lack of T cell recognition of tumor

production of immunosuppressive proteins or inhibitory cell surface proteins leads to

inhibition of T cell activation

oncogenic viruses

viruses that can develop into cancers

cause proliferation of the cells

kaposi sarcoma herpesvirus

causes Karposi sarcoma and seen in patients with AIDS

Human T-cell lymphotrophic virus

Adult T-cell leukemia

supresses T cell activation

epithelial-mesenchymal transition (EMT)

model for transition to metastatic cancer cells

usually in carcinomas

local spread of a tumor involves

cancer cell producing proteases that break down extracellular matrix and basement membranes

loss of adhesion molecules allow them to now spread into tissues

metastasis steps

1. Direct or continuous extension

2. Penetration into lymphatics, blood vessels, or body cavities

3. Transport into lymph or blood

4. Transport to secondary sites

5. Entry and growth in secondary sites

Epithelial-mesenchymal transition (EMT) produces which result?

increased resistance to apoptosis

paraneoplastic syndrome

medical condition caused by tumor secretions (hormones, cytokines, TNF, Interleukin-1), but not caused by the cancer itself

ex: hyponatremia, cushings syndrome, svc obstruction etc.

Eaton-Lambert Syndrome

autoimmune reaction to neuromuscular junctions causing neurological issues

small cell

more aggressive

associated with lung cancer

non-small cell

less aggressive

cachexia

loss of weight and generalized wasting that occurs during a chronic disease.

- muscle breakdown, atrophy, inflammation

- altered protein, lipid, carbohydrate metabolism