Loading presentation...

Present Remotely

Send the link below via email or IM


Present to your audience

Start remote presentation

  • Invited audience members will follow you as you navigate and present
  • People invited to a presentation do not need a Prezi account
  • This link expires 10 minutes after you close the presentation
  • A maximum of 30 users can follow your presentation
  • Learn more about this feature in our knowledge base article

Do you really want to delete this prezi?

Neither you, nor the coeditors you shared it with will be able to recover it again.


Make your likes visible on Facebook?

Connect your Facebook account to Prezi and let your likes appear on your timeline.
You can change this under Settings & Account at any time.

No, thanks


BSCI 245

Gretchen Wemhoener

on 14 April 2013

Comments (0)

Please log in to add your comment.

Report abuse

Transcript of Carcinogenesis

Carcinogenesis Gretchen Wemhoener Cancer development is a progressive process: mild hyperplasia advanced hyperplasia mammary epithelial cells HYPERPLASIA DYSPLASIA Precancerous cells undergo a change in morphology
as they grow and accumulate mutations. normal dysplastic METAPLASIA Excessively proliferating cells can invade the space
normally occupied by other types of cells. benign breach of
membrane Cancer cells metastasize
to new sites. Cancerous pancreatic islet
cells have metastasized to
a lymphatic vessel. Once across the basement membrane,
malignant cells invade nearby tissue. Malignant squamous epithelial
cells are invading the underlying
stromal tissue of the esophagus. malignant Precancerous cells proliferate at a
high rate, forming clusters. Evidence that cancer development is progressive: Patients who had their colon polyps removed
had a lower incidence of colorectal cancer than
patients who did not have polypectomies. Benign growths have been found adjacent
to malignant tumors. Tumors are monoclonal, implying
that a single cell has caused the
development of a cancerous mass. DNA mutations contribute to cancer development. Even if patients are heterozygous for G6PD, their
tumor cells contain only one allele of this protein. The Ames test shows a tight correlation between
mutagenicity and carcinogenicity of substances. Cells that have lost some of their natural defenses
against the accumulation of mutations become
cancerous at a higher rate than normal cells. A mutation in glutathione-S-transferase-π (a detoxifying agent) is linked to prostate
adenocarcinoma. Normally GST-π would prepare carcinogens for further metabolism by pairing them with glutathione. GST-π loss of GST-π
expression Dysfunctional DNA repair systems are correlated
with carcinogenesis. Xeroderma pigmentosum, which
is associated with a 1,000-fold
increase in skin cancer risk, is caused
by inherited defects in nucleotide
excision repair (NER) enzymes. Genomic instability allows cells to acquire new mutations that confer cancer characteristics. Cancer cells have some form of genomic instability:
The majority of colorectal cancer cells in this study showed chromosomal instability (CIN), and all of the
ones that did not have CIN showed microsatellite
instability (MIN). Gain-of-function mutations in proto-oncogenes promote tumor development. There are several types of changes that can convert proto-oncogenes to oncogenes. AMPLIFICATION Hundreds of copies of Myc were
found of chromosomes 6 and 9
of a neuroblastoma cell. OVEREXPRESSION A normal amount of DNA but large
quantities of RNA shows that erbB2/neu
gene is being overexpressed in this sample
from a human breast carcinoma. SMALL INTRAGENIC
MUTATIONS A single amino acid change in the
proto-oncogene H-ras causes it to
be constitutively active. CHROMOSOMAL
TRANSLOCATIONS In Burkitt's lymphoma, translocation of myc to
be next to IgH converts myc into an oncogene. A proto-oncogene encodes a protein that promotes cell division in a regulated fashion. A gain-of-function converts it to an oncogene and promotes cancer development. NUCLEUS CELL Within signaling pathways that control cell division, there are many proto-oncogenes whose mutation can lead to cancer development. Receptor tyrosine kinases, such as epidermal
growth factor receptor, can become constitutively
active by loss of their ectodomain or by a point
mutation in their cytosolic domain. Mutant constitutively active forms of the
Notch receptor are found in half of
adult T-cell leukemias. Mutant alleles of Patched and Smoothened
have been found in skin basal cell carcinomas. (many extra copies of a gene) (gene is transcribed more than normal) (incorrect base pair(s) within a gene) (exchange of segments of nonhomologous chromosomes) Familial breast and ovarian cancers are
often due to mutations in homology-
directed repair genes, such as BRCA1
and BRCA2. Mutations leading to cancer are not only found in membrane receptor proteins but also in the cytoplasmic signaling circuitry. Another example of this is the Ras pathway. The majority of genes in this path are proto-oncogenes. Ras RTK Grb2 Sos Normally, Ras is activated when
Sos unloads Ras's GDP and helps it
load GTP. Ras activates three primary pathways that can lead to cell transformation. growth factor normal pancreatic islet larger cells in
pancreatic islet with
constitutively active Akt A constitutively activating mutation in Akt allows cells to grow even if no growth factor has bound to the upstream
receptor. Akt activates mTOR, which stimulates protein
synthesis and thus increases cell size. anchorage-independent
growth A constitutively active component of the MAPK
pathway can allow cells to grow even if they are
not anchored to a substrate. Overactivation of Cdc42 can lead
to altered cell morphology by
causing filopodia extension. Aside from proto-oncogenes, there is another class
of genes called tumor suppressor genes (TSGs) that
is frequently found to be mutated in cancer cells. TSGs encode proteins that block progression through the cell cycle. Loss-of-function mutations or epigenetic events that decrease tumor suppressor expression can promote cancer development. One of the most important TSGs is Rb, which
acts as the master brake of the cell cycle. The stage of the cell cycle depends on the level of Rb phosphorylation. The cyclin D- CDK4/6 complex phosphorylates Rb. This hypophosphorylation makes Rb a good substrate for the cyclin E- CDK2 complex, which hyperphosphorylates it. When hyperphosphorylated, Rb permits the cells to pass through the restriction point. At this point, Rb releases the E2F transcription factors it had bound. E2Fs recruit histone acetylases, which decompact the chromatin to allow transcription of genes involved in nucleotide synthesis and replication. Dysfunction of the Rb pathway can happen in
various ways: -Excessive amounts of upstream mitogens and cytokines can cause cyclin-CDKs to phosphorylate (and thus inactivate) Rb more than normal.

-Loss of function in a CDK inhibitor can also cause the inactivation of Rb.

-Overexpression of the oncoprotein Myc involves two mechanisms for causing the hyperphosphorylation of Rb:
-Myc/Max activates expression of D cyclins and E2Fs.
-Myc/Miz-1 represses expression of CDK inhibitors. Another important TSG is p53.
It is a transcription factor that can induce cell cycle arrest in G1 or G2, can promote DNA repair, and in extreme conditions can induce apoptosis. p53 knockout mice have greatly increased
mortality compared to wild-type and
heterozygotic mice. p53 has many targets, a few of which are described here p53 GADD45 DNA repair enzyme p21 inhibitor of cyclin D/CDK4 that leads to GI arrest 14-3-3sigma scaffolding protein that
assists in G2 arrest Bax pro-apoptotic protein Mdm2 ubitquitin ligase that
regulates p53 levels Arf hyperproliferative
signals Normally, hyperproliferative signals would
lead to the activation of p53 so that the cell
would stop proliferating or, in severe cases,
undergo apoptosis. However, cancer cells often have a mutation in the p53 pathway that makes them unable to detect damage or signaling imbalances. Post-Irradiation Viability In this case, loss of p53 made the cells unable to apoptose after severe damage from irradiation. We've seen how cancer cells avoid apoptosis, but how do they become immortal? Normal cells die after a certain number of replications because they have lost their telomeres, the repetitive regions of DNA at the end of chromosomes that protect the genes from being lost as the genome shortens with every replication. Telomere collapse provokes a cell to enter crisis, in which it undergoes apoptosis. However, cancer cells can acquire the expression of hTERT (telomerase reverse transcriptase), which is responsible for lengthening telomeres. Expression of telomerase prevents cells from entering crisis. The evolution of tumors is often promoted by inflammatory signals, which can come from outside the cell itself... Tumors are heterogeneous and include the presence of cancer stem cells. Cancer stem cells account for a minority of the volume of a tumor, but only these (not other cells from the same tumor) are tumorigenic when injected into another organism. Cancer stem cells can be identified by their cell surface antigens. In this example of sorted cells from a breast cancer tumor, stem cells are marked by low CD24 expression but high CD44 expression. Cancer stem cells are relatively undifferentiated. They are the source of more stem cells along with transit-amplifying cells, which account for the vast majority of cell divisions within a tumor. Unlike in a transit-amplifying cell, a mutation within a cancer stem cell would not have a limit to its replicative ability, making it more likey to establish new clonal successions. Inflammatory stimuli cause recruitment of inflammatory cells & endothelial cells and their release of TNF-alpha. TNF-alpha activation of
NF-kB transcription
of COX-2 synthesis of
prostaglandins increased proliferation;
loss of E-cadherin Chronic inflammation often promotes
tumor progression: Apc-mutant mice fed prostaglandin E2 (a product of COX-2, thus a mediator of inflammation) showed a dramatic increase in the number of colon polyps compared with the control Apc-mutants. VEGF PDGF TGF-beta Angiogenesis is critical for tumor
development. When incubated with fibroblasts,
100% of the transformed cells formed
tumors and did so more quickly than
cells without fibroblasts. Cancer cells secrete signals, such as IL-6, that recruit macrophages, which release MMPs that free angiogenic factors from the matrix. MMPs VEGF PDGF TGF-beta MMPs CANCER AT THE
MULTICELLULAR LEVEL: Even precancerous cells can transmit angiogenic
signals to nearby stroma, providing a blood supply
for the new tumor as soon as the basement membrane is breached. blood vessels Metastasis Before cancer cells can metastasize to a new site, they must undergo an epithelial-to-mesenchymal transition (EMT) that gives them the ability to enter the circulatory system. EMT involves an decrease in expression
of epithelial markers and an increase in
expression of mesenchymal markers. After traveling through the circulatory system and reaching a favorable location to colonize, the metastatic cells can undergo a mesenchymal-to-epithelial transition (MET). Depending on the primary tumor from which they originated, cancer cells can spawn metastases in some tissues more easily than in others. macrophage One example of this is the NFkB pathway: Normally, NFkB is sequestered in the cytoplasm by IkB.
When IKK phosphorylates IkB, it is marked for degradation. Then NFkB can enter the nucleus and activate gene expression of many targets, including anti-apoptotic proteins, COX-2, cyclin D1 and Myc.

Constitutively active NFkB, often found in breast cancers, is useful for tumor formation because it leads to excessive cell proliferation and survival. p53 acts in response to DNA damage. In order to escape from senescence-a state in which the cell is metabolically active but unable to reenter the cell cycle- a cell must lose function of both p53 and Rb TSGs. Even aside from the inflammation response, stromal cells are essential for tumor growth. IL-6 Another way in which cancer cells interact with the stroma to promote their own growth is the Warburg effect: Mutual metabolic reprogramming between
carcinoma cells and surrounding fibroblasts:
Fibroblasts increase their glucose uptake and
lactate export. Carcinoma cells take up this lactate
and use it to fuel the Krebs cycle, which allows
them to proliferate. Intercellular communication via microvesicles can also induce cancerous transformation. Antonyak et al 2011 Heterotypic interactions between the stroma and cancer cells themselves are important to the process of metastasis. ANGIOGENESIS Microvesicles carrying fibronectin that has been crosslinked by tissue transglutaminase can induce a transformed phenotype in normal cells by activating the ERK and FAK pathways. This involves several types of stromal cells, which are responsible for acting on previously mentioned signaling pathways that lead to a transformed cellular phenotype. In this melanoma, the area
around each capillary (brown)
is healthy, but the area further
from the capillary is necrotic
due to lack of oxygen and
Full transcript