This document contains all the information you need to know to get a good grade on the biology of cancer exam. All the information from the lectures is in it, clearly defined and explained.
Summary Biology of Cancer
Lecture 1: Introduction to cancer
What is cancer?
Cancer is often a genetic disease: mutations lead to proteins with different function, overexpressed
protein, or no protein at all. It is a multi-step process where normal cells are transformed into cancer cells
that divide quite fast. Its Darwinian evolution is based on a growth advantage.
Benign vs. malignant
Tumors can be benign: the cells stay together in a closed
environment and remain localized at the site of their origin.
Tumors can also be malignant: cells invade the surrounding
tissue and spread (metastasis). Benign tumors are often called
cancer.
Cancers in different tissues
Cancers can originate in different tissues and are given different names based on its origin. There can be
adenocarcinoma (epithelial tissue of glands), squamous carcinoma (epithelial tissue), sarcoma (muscle
tissue and connective tissue), leukemia (hematopoietic system), gliomas (brain cells), and melanoma
(pigment cells). The place of the cancer matters for sensitivity to certain drugs. Cancer in lungs, colon,
stomach, and cervix happens most often (epithelial tumors). This is the case, because in these places, cells
divide fast (more chance of mutation), and are exposed to the environment for protection of the human
body. For every cancer type, there are often quite a lot of subtypes.
Origin of cancer
Most often, cancer originates from one abnormal cell, for example after
somatic mutations have occurred. Somatic mutations are not hereditary and
arise through chromosomal translocations, carcinogenic substances,
radiation, and viruses. An example of a somatic mutation is the presence of
the Philadelphia chromosome, which occurs through translocation of
chromosome 9 and 22. Cancer arises from accumulation of mutations over
time. Therefore, elderly people have higher chance of cancer than younger people. Sometimes, the
inactivation of one of the X chromosomes results in the formation of a monoclonal cancer.
Less abnormal cells
Some cancers develop from less abnormal cells: in cervical cancer there
can be pre-malignant lesions, and in colon cancer there can be polyps.
The process of cancer development is accelerated through consecutive
cycles of mutations (genetic or epigenetic inactivation of genes),
although not all mutations are vital. Sometimes cancer can arise from a
cancer stem cell. It can also be accelerated by genetic instability (like
chromosomal translocations), decreased apoptosis and differentiation,
increased proliferation, and independence from the environment (allows
metastasis).
External risk factors
External risk factors for cancer are UV light, smoking, drinking, radiation,
diet, and infection (HIV, HPV). Because this is different in every country, the cancers are also different for
,every country. Mutagenesis is researched by Ames test: the liver extract of a rat
(which contains many proteins, also CYP), with Salmonella strain and a
possible mutagen, is put on a plate with minimal histidine (required for
Salmonella). If there is a high number of revertant (his- to his+), a lot of
mutations have taken place, and the mutagen is probably mutagenic.
Examples of factors and their related cancers are U.V. that causes
melanoma, asbestos that causes mesothelioma, and HPV that causes
cervical cancer.
Cancer causing genes
Genes that are often mutated and related to cancer are oncogenes and tumor suppressor genes. The
cancer-causing genes have been identified by Peyton Rous, that
isolated sarcoma from chicken and injected it into young chicken:
cancer was formed as well. So, there must be something in the
tissue (DNA) that causes it. Later it became clear that viruses could
cause cancer by inserting DNA genes: v-oncogenes (v-onc).
Identification now can be done by growing tumor cells in a flask, and if they grow on top of each other it is
a tumor (overcoming cell-cell contact inhibition).
Oncogenes
Oncogenes have a gain-of-function mutation, with a dominant growth-
stimulating effect. Often the gain of function arises through RAS deletion
or mutation, Myc amplification and overexpression, or chromosomal
rearrangement of Bcr-Abl (the Philadelphia chromosome, leading to a
gene under control of another promoter). RAS, Myc and Bcr-Abl are
oncogenes themselves. A single mutation event can already create an
oncogene, that is why oncogene mutations are not hereditary: the embryo would not be vital. When there
has not yet been a mutation, the gene is called a proto-oncogene. Oncogenes in the host chromosome are
called c-oncogenes (c-onc). The oncogenes often lead to altered signaling pathways in cancer.
Tumor suppressor gene
When working normally, tumor suppressor genes prevent tumors from
occurring. Therefore, mutations in this gene lead to loss of function. Two
mutations are necessary for the full inactivation of the tumor suppressor
gene. When there is already one mutation, that has for example been
inherited, it is easier to gain the second mutation. This was also explained by Knudson’s two hit hypothesis
(1971): the chance for inactivation of the Rb gene is greater in people who have already inherited a
mutated form of Rb gene from their parents. Also for the tumor
suppressor genes, there are changed signaling cascades due to
the loss of function. There can be inactivation of Rb, inactivation
of p53 (both important in the cell cycle), and there can be
inactivation of APC (in the Wnt signaling pathway, leading to
continuous active β-catenin).
In the colon, there is first APC loss, causing a pre-malignant
lesion. P53 mutation occurs only later. This is specific and important for the type of cancer. Familial
adenomatous polyposis (FAP) has a lot of polyps that are moderately malignant (high chance of cancer)
and Hereditary nonpolyposis colorectal cancer (HNPCC) have scarce polyps but very malignant.
It would be best to prevent all cancers, but treatment is easier. Vaccination is an easy way to prevent, and
chemoprevention is also done but also causes a lot of side effects (COX2 inhibiter removed from the
market). They must be used for a prolonged period, and the effectiveness must outweigh the toxicity.
, Lecture 2: Oncogenes, growth factors, and signaling circuits in cancer
Malformations were already described before Christ. In the early 20 th century, Yamagiwa found that
extrinsic factors can cause cancers (like chemicals and radiation). In the 70s it was thought that cancer
might be caused by viruses. However, most cancers are not caused by infections, and cancer is not an
infectious disease. Only recently researchers found that there are genes that cause cancer: oncogenes and
tumor suppressor genes.
Oncogenes
Oncogenes are mutated genes that contribute to the development of cancer. In a non-mutated state, it is
called a proto-oncogene and plays a role in the regulation of cell division. In tumor suppressor genes the
opposite occurs: it has a function in the prevention of tumor development. However, upon mutation, this
function is lost, and uncontrolled cell growth occurs.
Copy number variations
An example of an oncogene is erbB, which is found in the Avian
erythroblastosis virus in mice and can cause gastric, lung, and breast cancer
in humans. ErbB2 is also called HER2, and shows poor prognosis of breast
cancer, if the gene is amplified (more than 2 dots in the FISH technique:
more than 2 alleles of the gene). Also, CyclinD1 was amplified. More
amplification of oncogenes leads to more aggressive disease progression
(and therefore poor prognosis). For some cancers, copy number alterations
are found on more than one chromosome, for other cancers they are only
found on one chromosome, and in this case often a very specific gene is the
cause of the cancer. Another example is the N-myc oncogene, which also
leads to cancers like neuroblastomas and lung carcinomas when amplified.
Mutations in proto-oncogene
In some cases, genes are not amplified, but mutations have taken
place. An example is a mutation in the RAS gene, where a single bas-
pair mutation can change the proto-oncogene to an oncogene.
Normally RAS binds GDP in the inactive state, and is changed for GTP
upon activation, acting as an on-and-off switch. A mutation in the
binding pocket of GTP leads to greater affinity for GTP, making the RAS
molecule continuously active and independent of signals from the
outside. The three RAS genes are H-RAS, K-RAS, and N-RAS, and they
can all be mutated in tumors.
Identification oncogene among 22.000 normal genes
To identify oncogenes, we can do an experiment. First, DNA is
isolated from transformed (exposed to chemicals) mice
fibroblasts. The DNA is cut into pieces and transfected into
normal cells. The cells are grown, and cells with a normal gene
form normal colonies. Cells with mutations in the oncogenes
form colonies that grow on top of each other. Isolation of these
colonies leads again to formation of a tumor in mice. The experiment can also be done with a real tumor.
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