Carcinogenesis Initiation and Progression

Question 1

Sporadic Cancers

• __% of cancers
• Mutations in what type of cells?
• ___ family history
• ___ age of onset
• ___ primary site

Answer 1

• 99
• somatic
• No
• Typical (i.e. not early)
• Single

Question 2

Hereditary Cancer

• __% cancers
• Mutations present in what cells?
• __ family history
• __ age of onset
• location

Answer 2

• 1
• Inherited from parents, so present in parents germline cells
• Positive
• Early
• Bilateral or multifocal

Question 3

Oncogene

Answer 3

A gene that causes cancer, that is associated with cancer and are subject to activating mutations.

Question 4

What is a proto-oncogene?

Answer 4

Normal genes that are the target of the activating mutations that ultimately give rise to oncogenes and/or abberant expression

Question 5

Do viral oncogenes have proto-oncogenes?

Answer 5

Not all - some viruses lack proto-oncogenes

Question 6

Tumor suppressor

Answer 6

Gene whose product acts to inhibit cancer and are ianctivated by cancer by mutation/deletion or epigenetic silencing

Question 7

Tumor suppressors are subject to ______ mutations

Answer 7

Loss of function

Question 8

Most hereditary cancers are associated with mutations in _____ genes

Answer 8

Tumor suppressor

Question 9

Oncogenes are always a ____ of function

Answer 9

Gain

Question 10

Oncogenes and tumor suppressors often act in the (same/different) pathways

Answer 10

Same

Question 11

Describe the darwinian model of cancer initiation and progression.

Answer 11

An initiator (UV radiation, chemical agent, virus, etc.) induces mutation that confers higher proliferative potential. Tumor promoters stimulate proliferation and produce a pool of altered cells. With increased proliferative rate the cells are more likely to acquire additional mutations. Continued expansion of cell pool allows additional mutations to arise and it is suggested that cells in these populations with new mutations that confer proliferative advantage are progressively selected in subsequent rounds of division.

Question 12

What is a genotoxic carcinogen?

Answer 12

Something that damages DNA/alters DNA

Question 13

What is a mitogenic carcinogen?

Answer 13

Something that has an effect on proliferative ability of cells

Question 14

Adenomatous Polyposis Coli (APC)

• What is the inheritance pattern?
• What occurs in these patients during their teens? During their mid-adult life?

Answer 14

• Autosomal dominant
• Polyps…colorectal cancer

Question 15

What does a loss of function at the APC locus result in? What type of gene must APC be?

Answer 15

Promotion of proliferation and inhibition of differentiation

Tumor suppressor

Question 16

Describe how APC functions in Wnt signaling.

Answer 16

Wnt (ligand) Absent

Without Wnt signaling, APC binds to Beta-catenin. This complex is bound by Glycogen Synthase Kinase 3, which phosphorylates Beta-catenin. This phosphoyrlation targets Beta-Catenin for degradation by proteasome. Beta-catenin is needed to bind to transcription factor, TCF, which is always bound to promoter. Without Beta-catenin, there will be no transcription so APC is a tumor suppressor.

Wnt (ligand) Present

When Wnt is present, Wnt binds to frizzled receptor and results in sequestering of proteins that are involved in destruction of Beta-catenin (GSK3). This allows Beta-catenin to accumulate b/c it is not being phosphorylated so it is transported to the nucleus. In nucleus, Beta-catenin binds TCF on promoter and recruits histone acetyltransferases that results in transcription of gene.

Question 17

What are the target genes of Beta-Catenin?

Answer 17

Regulators of cell cycle and proliferation

Regulators of differentiation

Regualtors of stem cell phenotype

Question 18

Discuss the heterogeneity that is seen in cancers.

Answer 18

Cancers of a specific cell type in a specific tissue are not composed of identical cells. Mutations can hit one gene that causes cancer, and then a later daughter cell from that original cancerous cell can acquire a different mutation that also causes cancer so you can have mulitple cancer causing mutations even within the same population of cancerous cells.

Question 19

What is the general concept of the epithelial to mesenchymal transition?

Answer 19

Epithelial cells begin to look and act more like fibroblasts due to epigenetic and genetic changes that lead to changes in cell polarization

Question 20

Describe the process of the EMT.

Answer 20

Cancer cells begin to lose their normal epithelial attachments through loss of E-cadherin. They then degrade the basement membrane and ECM by releasing metalloproteases (MMPs). This results in a release of growth factors imbeded in the ECM. The cancer cells then express integrins that bind to the ECM (fibronectin). This allows the cancer cells to recruit stromal cells and ultimately invade the tissue.

Question 21

Explain how the TGF-Beta pathway is exploited by cancer cells.

Answer 21

One action of TGF-beta signaling is to stimulate stromal fibroblasts to produce collagen. The cancer cells can hijack this pathway and use it to react with stromal cells to generate connective tissue for the growing cancer.

Question 22

What is this structure and what is its role in carcinogenesis progression?

Answer 22

Necrotic center is disorganized and not properly vascularized.

Question 23

____ is the driver for additional malignant changes.

Answer 23

Hypoxia

Question 24

Describe how cells sense hypoxia.

Answer 24

There is a protein called HIF-1alpha (hypoxia inducible factor alpha). Under normal conditions, when it is translated, it is hydroxylated which targets it for degradation by the proteasome. Under hypoxic conditions the hydroxylation is not able to occur so H1Falpha migrates into the nucleus and acts as a transcription factor. HIF-1alpha is an inducible TF.

Question 25

How does hypoxia relate to angiogenesis in the setting of cancer.

Answer 25

At least some of the genes that are induced by HIF-1alpha are genes that induce angiogenesis. When cancer cells proliferate, they consume require oxygen to continue survival but they have no inherent blood supply. As such, their local environment is hypoxic so they trigger HIF-1alpha signaling to induce angiogenesis for themselves.

Question 26

What is desmoplasia?

Answer 26

The growth of new fibrous connective tissue. This term can be used to refer to a cancer cell’s ability to manipulate stromal cells into making collagen for the cancer to grow.