neoplasm II Flashcards
Molecular Basis of Cancer
Neoplasms are cells that have escaped
normal growth regulation to proliferate
autonomously
-these masses of proliferating cells can be benign or malignant
-cancer refers to a malignant neoplasm
-continual proliferation occurs at the detriment of normal tissues
Autonomous growth
means proliferation in the absence of growth promoting signals or in spite of growth inhibitory signals
-neoplasms do not need exogenous growth
factors
-neoplasms grow even in the presence of growth inhibitory signals (i.e. contact inhibition) or genetic damage that would normally induce apoptosis (absence of p53 function)
What is needed to for a normal cell to become neoplastic (transform)?
- A cell that has the potential to divide
- A mechanism for DNA damage
- Damage to a relevant genes
- Damage to the mechanisms that keep cells
from replicating if they have damaged DNA - Once damaged, the cell must experience a
proliferative signal to start the autonomous
proliferation - Neoplasms need their own blood supply
- In order for cells to leave the tumor mass for
metastasis or inflitration of surrounding tissues, it
must have the capacity to move, lyse ECM, and
adhere to specific cell types (like endothelium)
A cell that has the potential to divide
myocardial cells, neurons do not form cancers -the more a tissue divides, the more likely it is to give rise to a cancer: -skin -mucosal or ductal epithelium -lung, breast, colon -bone marrow -leukemias, lymphomas
A mechanism for DNA damage
- chemical carcinogen: reactive molecular species
- radiation: energy or particle damage to DNA
- chronic inflammation: free radical formation
- insertion of viral oncogenes
Damage to a relevant genes
-target genes are involved in growth regulation
or control of DNA transcription
*growth factors, growth factor receptors, signal
transduction mechanisms (RAS), kinase cascade
elements, transcription elements
*genes associated with cancer formation are called
oncogenes
-damage to genes that are not involved in growth
or never expressed is irrelevant
most common cause of cancer in US
skin cancer
Damage to a relevant genes
-damage can result from mutation, rearrangement of elements (chromosomal breakage) or gene reduplication -cells that do not have DNA repair mechanisms are at greater risk of DNA gene damage (xeroderma pigmentosum) -usually damage to multiple genes is required -carcinogenesis is a stepwise process
Damage to the mechanisms that keep cells
from replicating if they have damaged DNA
- tumor suppressor genes
- damage to p53 is involved in most human visceral cancers and is thought to be late in a step-wise process
- mutations in Rb or other apoptotic proteins may inhibit apoptosis of damaged cells
- retinoblastoma – two hit hypothesis
Once damaged, the cell must experience a
proliferative signal to start the autonomous
proliferation
_continuously proliferating tissues, tissues responsive to hormones, and tissues undergoing chronic inflammation are at greatest risk of giving rise to an autonomous population
*lung, breast, prostate, liver, bone marrow, skin, etc.
most common cause of cancer than is mediated by ROS
chronic inflammation
3 important things needed to for a neoplasm?
- Damage to relevant genes – initiation
- Expression of damaged relevant genes – promotion
- Initiation must occur before promotion
Neoplasms need their own blood supply
Neoplasms need their own blood supply.While individual cells are autonomous, the they still require nutrients and oxygen
-tumor masses greater than about 16 cells require that the neoplastic cell is making angiogenic factors to supply the tumor mass with new blood vessels
viral oncogenes are from
DNA
In order for cells to leave the tumor mass for
metastasis or inflitration of surrounding tissues, it
must have the capacity to move, lyse ECM, and
adhere to specific cell types (like endothelium)
in the absence of these properties, the autonomous cells create a stable (but growing), benign mass
-in malignant tumors, individual cells begin to
express new features (unstable) and select for
traits that contribute to survival and separation
-individual cells leave the parent clone (malignant
tumor), enter the bloodstream or lymphatics, and
migrate to other tissues
summary: What is needed to form a cancer?
- A cell that has the potential to divide
- A mechanism for DNA damage
- Damage to a relevant genes
- Inhibition of tumor suppressor mechanisms
(damage to tumor suppressor genes) - Proliferation of damaged cells
- Angiogenesis
- Ability to metastasize (malignant)
what do the steps in order to form neoplasms explain about neoplasms and how they go?
-Neoplasms occur more often in some tissues than
others
-There are well-known associations between
cancers and exposures to things that cause DNA
damage
-Not all exposures result in cancer
-It takes time: stepwise damage to genes in proliferative pool and most cancers occur in older adults unless there is a gene mutation (familial or congenital) that starts them on the path much earlier
in summary, neoplasms:
- A neoplasm results from DNA damage that allows for the -expression of genes (and loss of growth inhibition) that interfere with normal growth control mechanisms, resulting in autonomous growth of a single cell into a clone of cells.
- This process is at best random, but with sufficient exposure to things that cause DNA damage and enough time, of billions of cells that are damaged and proliferate, it is not surprising that after decades, the multiple specific gene defects that allow for cancer growth will eventually develop.
General Principles of Oncogenesis
- Escape from normal growth regulation occurs as the result of non-lethal genetic alterations
- genetic alterations can only be expressed if the cell subsequently undergoes cell division
- Tumors are formed by the clonal expansion of a single cell
- Cells proliferate following activation of specific growth regulatory signals
- DNA repair genes influence the cell’s ability to repair non-lethal damage
- Damaged cells must escape from apoptotic mechanisms that are designed to keep damaged cells from dividing
- For a cell to go from regulated growth to totally unregulated growth is a multistep process
Escape from normal growth regulation occurs as
the result of non-lethal genetic alterations
alterations in DNA can result from actual damage, structural changes, or functional alterations
-in order for expression of altered DNA to result in a viable cell, the alterations must not alter essential structures or functions of the cell:
*only a small number of genetic alterations result in a cell
that can undergo continual proliferation – the vast majority are lethal to the cell or are never expressed
what percent of DNA alterations are expressed or lethal to a cell?
99%
- anti-cancer therapies (chemotherapeutic drugs and radiation) work by inducing DNA mutagenesis that is nearly always lethal to dividing cancer cells
- children who receive cancer therapy often develop secondary cancers as an adult, presumably from mutations caused by the chemotherapy or radiation
genetic alterations can only be expressed if the
cell subsequently undergoes cell division
- in the absence of cell division, genetic alterations cannot be expressed
- both genetic damage and induction of cell proliferation must both occur for establishment of autonomous growth
early tumors are almost always
localized (stage 1)
late tumors are almost always
metastasis (stage 4)
Tumors are formed by the clonal expansion
of a single cell
- clonal implies that all of the cells originated from a single cell (neoplasms are monoclonal rather than oligoclonal or polyclonal)
- however, clonal expansion does not mean that all of the daughter cells are exactly the same
- badly damaged cells are unstable and daughter cells can develop new properties
how can Clonality be established?
-by examining the expression of specific alleles in the
daughter cells
markers for clonality
-markers of clonality include methylationpatterns of specific genes or indicators of identical gene rearrangements such as immunoglobulin and T-cell isotypes
Cells proliferate following activation of specific
growth regulatory signals
-regulatory elements can be positive or inhibitory
-activation of signaling pathways can promote
autonomous growth
-loss of inhibitory signals can also promote growth
-growth regulatory elements are the primary targets of
genetic damage in neoplasms
what are the Four classes of normal regulatory genes that are genetic targets for alterations and result in autonomous proliferation of cells?
- growth-promoting proto-oncogenes
- growth-inhibiting tumor suppressor genes
- genes that regulate apoptosis
- genes involved in DNA repair
Oncogene
oncogenes are genes that have been identified
to be altered in many forms of cancer
-these genes generally involved regulatory elements
of growth - growth factors, growth factor receptors,
GTPases, kinases, transcription elements, etc.
proto-oncogene
oncogenes are mutated forms or un-expressed versions of normal genes
- non-altered gene present in normal cells is know as proto-oncogene
- during carcinogenesis, proto-oncogene become expressed as oncogenes
dominant oncogenes
- elements that promote growth only need expression of a single allele to cause unregulated proliferation
- these oncogenes are considered to be dominant
- Example: mutated growth factor receptors
recessive oncogenes
-elements that inhibit growth requires loss of
both alleles to eliminate the inhibitory signal
*tumor suppressor genes are considered to be
recessive
Dominant oncogenes promote
GROWTH
-include RAS, growth factors, growth factor receptors,
etc.
-you only have to gain 1 copy to promote growth
Recessive oncogenes suppress
GROWTH
-tumor suppressor genes or anti-oncogenes include
p53, RB, etc.
-you have to lose both copies of the normal gene to
eliminate suppression
DNA repair genes influence the cell’s ability
to repair non-lethal damage
Inhibition or loss of DNA repair mechanisms plays an important role in the retention and expression of damaged regulatory elements:
-damaged cells must undergo repair prior to
proliferation
-cells with extensive unrepaired DNA damage may
undergo apoptosis
DNA Repair Genes
-Considered to be tumor suppressor genes
-Loss of both alleles are necessary to totally inhibit or lose capacity to repair DNA (recessive):
-individuals who inherit a mutated allele for
DNA repair mechanisms are at greatly
increased risk of developing cancer (if they lose the other allele)
-Xeroderma pigmentosum
Damaged cells must escape from apoptotic
mechanisms that are designed to keep
damaged cells from dividing
- damaged cells must either be repaired or undergo apoptosis – this prevents damaged cells from replicating
- loss of functional p53 or Rb proteins are important steps in allowing damaged cells to divide rather than undergo apoptosis
- telomeres do not shorten in immortal cell lines
For a cell to go from regulated growth to
totally unregulated growth is a multistep
process
both constitutive expression of multiple positive
growth signals and loss of inhibitory growth signals:
-cells with genetic damage are usually inhibited or
undergo apoptosis
-loss of these inhibitory mechanisms permits growth
of previously damaged cells
transformation
Attainment of the capacity for autonomous growth
- exposure to chemicals (carcinogens) or radiation causes DNA damage in vitro that results in the development of a small number of autonomous clones of cells
- it is assumed that a similar process occurs in vivo as a result of environmental exposure to carcinogenic elements
cells are determined to be transformed in vitro when
*Grow without the addition of growth factors
*Form continually proliferating colonies that override normal contact inhibition signals:
-show no contact inhibition
-grow in soft agar
-form three-dimensional colonies rather than a
monolayer
monoclonal
all from one cell
oligoclonoal
most responses to infectious agents
polyclonal
in lupus
Normal Cells
- Divide only with mitogenicsignal
- Apoptosis or growth inhibition of damaged cells
- Stable genome
- Telomeres shorten with proliferation
- Contact inhibition
- Monolayer growth
- Few cell capable of angiogenesis
Transformed (neoplastic) cells
- Divide independent of mitogenic signals
- Damaged cells free to divide
- Unstable genome (including chromosomal instability)
- No shortening of telomeres
- No contact inhibition
- Grow in aggregates
- Induce angiogenesis
how do Malignant cancers differ from benign tumors
-ability to separate from the original colony to invade
underlying tissues and form distant metastases
-development of invasive phenotypes reflects underlying
genetic instability and selection of clones with new
phenotypes
what do malignant tumors show more of?
more genetic variability, more genetic instability
- Anaplasia, pleomorphism
- Invasion, metastasis
Benign tumors are
- More like parent cells in morphology and functions
- Cells remain in association with original colony
- Little clonal variation
Malignant tumors are
- Less like parent cells; rarely functional
- Cells separate and migrate away from original colony:
- Invasion
- Metastasis
- Genetic instability results in variation in structure and function
untreated malignant tumors will lead to?
death of the organism
when are Benign tumors life threatening?
- expansion within a closed space (skull)
- obstruction of a space or outflow tract
- overproduction of a hormone or other protein
