BLD 204 Exam 4

neoplasm

a new growth. It is usually abnormal, a mass of tissue, disorderly cells that have disorderly cell proliferation, differentiation and relationship to the surrounding stroma.

-normally there are controls for cell division
-normally cells only divide a certain number of times, only fill so much space and they do this in the right location

normal cell proliferation characteristics

-the cells escape the controls for normal cell division
-they can become basically immortal, dividing many many more times than they should
-the end result is a mass of cells in an inappropriate number in an inappropriate location

disorderly cell proliferation characteristics

-normal cell differentiation is orderly
-it progresses until the cell has reached its normal function and structural characteristics
-tissues are also organized in an orderly fashion
-restriction of the expression of the genome of individual cells allows all of this to happen

characteristics of normal cell division

-neoplastic cells fail to differentiate properly
-they often remain stuck in more immature states
-the more immature the worse the outcome
-immature, undifferentiated cells exhibit behaviors that they shouldn't like expressing fetal proteins or hormones

disorderly differentiation characteristics

-don't invade surrounding tissue
-no metastasis
-growth rate low
-little mitosis
-some atrophy of surrounding tissue by pressure of the mass

biological behavior of a benign neoplasm

-invade surrounding tissue
-metastasis
-lots of mitosis and growth
-damage surrounding tissue

biological behavior of malignant neoplasm

malignancy

invasive, abnormal tissue formations. Increased proliferation and abnormal cell division. Incomplete differentiation where cells vary in size and shape. Nuclei have greater volume than normal in proportion. Abnormal ploidy

carcinoma

malignant tissue/tumor in the epithelium

sarcoma

malignant tumor of connective tissue

dysplasia

cell changes indicative of malignancy but no invasion present yet. It's a warning sign. Common in epithelial tissue.

carcinoma in situ

If the whole depth of the epithelial tissue is dysplastic this is what it is called

hamartoma

tumor like mass that lacks autonomous behavior. Good differentiation and in the right organ. Organization is different from normal. Vascular is the most common

heteroplasia

differentiation of tissue is wrong for the location. Not metaplasia, no change from one fully differentiated form to another. Happens at the stem cell change. Just a mass that doesn't belong there. Masses of various types or one type of tissue.

papilloma

Benign epithelial cells growing in a sheet. Squamous, transitional or columnar.

papilloma and adenoma

benign epithelial neoplasms

adenoma

benign solid islands or masses of cells, arise from the gland or duct epithelium. Because of the source tissue, small groups of cells gather around a lumen but there is no real drainage so a cyst may develop.

G1 -> S -> G2 -> M

cell cycle

G1

phase of cell cycle where cells are not resting like in G0. It can be a very long stage, depends on the cell type. Cells that remain in the cycle are termed being in the growth fraction.

S

phase of cell cycle where DNA synthesis occurs

G2

premitotic phase of cell cycle

M

phase of cell cycle where cells are actively undergoing mitosis

cyclins, cyclin dependent kinases and CDK inhibitors

controls of the cell cycle

hyperplasia

an increase in the number of cells. It is a response to an increase in functional need. Controlled by negative feedback mechanisms

congenital adrenal hyperplasia

hyperplasia with early manifestation. masculization of females, early puberty for males. Salt loss. There are defective adrenal cells which causes decreased cortisol and aldosterone, increased adrenocorticopic hormone from pituitary. Makes more adrenal cells which still doesn't work, built up precursors of hormones get used for steroid production instead

thyroid hyperplasia

hyperplasia caused by an abnormal stimuli or a problem with feedback for TSH. It causes a goiter.

hypertrophy

increase in cell size, it occurs in muscle, the uterus during pregnancy, bladder when the urine outflow is obstructed and heart with increased workload.

atrophy

decrease in bulk due to decrease in demand. Physiological occurs during development especially (ex: in the thymus). Osteoporosis occurs with increased reabsorption, decreased synthesis or both, weight bearing exercises increases demand and helps you lay down bone.

-non neoplastic changes cease when the stimulus is removed
-neoplastic changes don't respond to normal stimuli
-autonomous behavior

difference between neoplastic and non-neoplastic changes

transformation

this refers to cells that have changed into neoplastic cells and exhibit all that behavior. These cells don't show contact inhibition in cell culture.

-normal cells recognize each other, communicate about division, adhere to each other.
-neoplastic cells have a failure of inhibition signals that would restrain proliferation or increased growth factor expression encourages them to proliferate (autocrine, ex: TNF alpha, PDGF) or both things happen

cell communication/proliferation neoplastic vs. normal

-neoplastic cells lose morphology and orientation of mature cells (ANAPLASIA)
-cells that have the most potential to divide in the body are in the stem cell compartment

cell differentiation differences, neoplastic vs. normal

anaplasia

a change in the structure of cells and in their orientation to each other

-DNA to RNA: transcriptional control
-RNA: processing, transport, degradation/stabilization
-RNA to protein: translational control, control of proteins
-environmental control: interactions between cell types, same cell to cell interactions.

controls for daughter cells gene expression

-not fully differentiated
-because they haven't committed to a pathway they can still divide
-the differentiation can be heterogenous
-serious lack of differentiation results in anaplasia

transformed cell differentiation differences

-Self sufficiency of growth signals
-Insensitivity to growth inhibition
-Evading apoptosis
-Limitless replicative potential
-Sustained angiogenesis
-Tissue invasion and metastasis
-reprograming energy metabolism
-evading the immune system

hallmarks of cancer

most growth factor action on normal cells is paracrine. Cancer cells make their own or they tell the stroma to make them some.

cancer cells growth factors (self sufficiency of growth signals)

cancer cells overexpress these receptors or they have mutated receptors that are "always on" sending signals continuously even without growth factors. Examples of this is overexpression of EGF (occurs in squamous cell carcinomas of lung, glioblastomas and epithelial tumors of head/neck) and similar overexpression of ERBB2 (happens in some breast cancers)

cancer cells and growth factor receptors (self sufficiency of growth signals)

mutations occur further downstream, on the signally proteins inside the cell. Direct stimulation of signal to the nucleus without growth receptor signal. Two most common mutations are in RAS and ABL.

Cancer cells and signal tranducing proteins (self sufficiency of growth signals)

RAS

signal tranducing protein, most commonly mutated gene in human tumors. Small protein that binds GTP and GDP

ABL

tyrosine kinase. Translocation in chronic myelogenous leukemia from chromosome 9 to 22. fuses with BCR (breakpoint cluster region) there and makes fusion protein that has constitutive activity

cancer related mutations in transcription factors can result in expression of more growth promoting genes like growth factor genes. Ex: MYC

nuclear transcription factors and cancer cells (self sufficiency of growth signals)

MYC

nuclear transcription factor that activates or represses. It activates genes that encourage progression through the cell cycle like cyclins. It represses genes that repress genes that prevent it. Encourages aerobic glycolysis and glutamine utilization. Mutation of it is seen in Burkitt's lymphoma

cyclins

regulate progression through the cell cycle

cyclin dependent kinases

activated by binding to cyclins, maintain orderly progression

cyclin-dependent kinase inhibitors

broad and selective inhibitors of CDKS

-growth factors
-growth factor receptors
-signal tranducing proteins
-nuclear transcription factors
-cyclins and cyclin dependent kinases

what factors play into the self sufficiency of growth signals hallmark of cancer?

-all cancers seem to have mutations that disable the G1-S checkpoint
-increases cyclin D and CDK4 expression
-CDKIs disabled by mutation or silenced

cyclins and cyclin dependent kinases and cancer cells (self sufficiency of growth signals)

tumor supressor genes

brakes for proliferation. The result of mutations in this system is very similar to self sufficiency of growth signals

-RB (retinoblastoma protein)
-TP53 (tumor protein 53)
-TGF beta (transforming growth factor beta)
-contact inhibition pathways

four major gene targets of insensitivity to growth inhibition signals

RB

DNA binding, regulates the G1-S checkpoint. Important in development, cell cycle "clock" once past, they must divide eventually. Fairly common mutation. Many viruses which are oncogenic bind this (ex: HPV). This is the gene implicated in retinoblastoma which is a rare childhood cancer

TP53

monitors cell stress. Anoxia, DNA damage, inappropriate signaling. Encourages transcription of CDKI which inhibits the cell cycle. Blocks G1 to S for a time for repairs. If no repair, induces senescence or apoptosis. Viruses can subvert it just like RB (ex: HPV)

TGF beta pathway

normal proliferation inhibitor in epithelial, endothelial and hematopoietic cells. Mutations in 100% of pancreatic cancers and 83% of colon cancers. This is a loss of function of inhibitor

contact inhibition

cadherins mediate cell to cell contact. NF2 gene product merlin facilitates E cadherin contact inhibition. APC gene product loss also can be involved in loss of this by destroying beta catenin which can be a growth promoting transcription factor.

TCF is continually activated

loss of function of APC leads to cell proliferation because...

BAX-BAK pro apoptotic action is regulated by BCL2 which is anti apoptotic. BCL2 mutations that activate it are common in B cell lymphomas. When BCL2 is always activated (like in cancer) apoptosis won't occur. Cancer cells also avoid autophagy by mutation or take it over to get parts to grow.

evading apoptosis

60-70

max number of cell divisions is usually...

Short telomeres are recognized as dsDNA breaks leading to senescence mediated by RB and p53

how does senescence occur?

RB and p53 are inactivated and the ends of the two chromosomes get connected in a last ditch effort at repair, this leads to dicentric chromosomes which lead to mutations.

limitless replicative potential (the big picture)

telomerase

usually only present in stem cells. It maintains telomere length. It can be reactivated to maintain telomere length in cancer cells (85-95%)

-constant proliferation leads to telomere shortening
-telomere shortening leads to bridge fusion breakage cycle when p53 is absent
-BFB cycle leads to mutation
-telomerase is reactivated, fixing mutations and allows the cells to continue dividing

limitless replicative potential model

Vascularization

tumor bigger than a 2mm can't survive without...

-neoangiogenesis: new sprouts from capillaries in the area
-vasculogenesis: endothelial cells come from the bone marrow to make blood vessels

how are tumors vascularized?

hypoxia stimulates productions of pro-angiogenesis cytokines like VEGF which happens through the activation of HIF-1 alpha. Unless there is hypoxia, HIF-1 alpha is controlled by VHL which binds its signaling for destruction. If there is hypoxia, VHL no longer binds HIF-1 alpha.

development of sustained angiogenesis: hypoxia

Thrombospondin-1 (TSP-1) is produced by stomal fibroblasts and synthesis is induced by p53. Protease produced angiostatin, endostatin and vasculostatin

development of sustained angiogenesis: inhibitory factors

loss of p53 causes loss of TSP 1, VHL mutations are associated with renal cancers, cancer cells produce VEGF and proteases that can swing the balance.

development of sustained angiogenesis in cancer

metastasis

second tumor site with no continuity with the first. Spread via the lymphatics or the blood stream

most common in carcinomas (ex: breast or malignant melanoma). Invades the lymphatic vessels and spreads up along the lymphatic vessel to the node. The blood stream and lymphatics are connected

lymphatic spread (ability to invade and metastasize)

most common in sarcomas. Invasion can happen in the tumor's new blood vessels or in nearby vasculature

spread via bloodstream (ability to invade and metastasize)

1. liberation
2. invasion
3. transfer as emboli
4. adhesion at endothelium
5. migration from the vessel
6. survival (angiogenesis)
7. multiplication and growth

steps of metastasis

GI and pancreas, spread via blood vessels

most common source of liver cancer

-liver
-skeleton
-brain
-lung
-adrenals

common secondary sites for metastasis

breast, prostate, kidney, thyroid

common sources of skeleton cancer

lung is most common, also breast and adrenals

common source of brain cancer

breast and stomach carcinomas and sarcomas

common source of lung cancer

lung and breast

common source of adrenal cancer

loss, gain

(gain/loss) of p53 and (gain/loss) of telomerase causes unlimited replicative potential

-anaerobic glycolysis (Warburg Effect)
-Favored when rapid growth is required

reprograming energy metabolism

-most cancer patients are immunocompetent until treatments

evading the immune system

-growth promoting proto oncogenes
-growth inhibiting tumor suppressor genes
-genes that regulate apoptosis
-genes that are involved in DNA repair

four classes of regulatory genes that are targets of genetic damage

oncogenes

genes that include a transformed phenotype when expressed in cells. Usually mutated or overexpressed versions of normal genes proto oncogenes. DOMINANT: single allele is sufficient for transformation

tumor supressor genes

genes that normally suppress uncontrolled growth. When they are mutated or lost, the transformed phenotype appears. Usually, both alleles have to be damaged for the phenotype to appear but sometimes a single allele will do it (haploinsuffiency). There are two types, governors and guardians

governors

type of tumor suppressor gene where a mutation removes an important stop mechanism (RB)

guardians

type of tumor suppressor gene that produces proteins that act as sensors of genomic damage (p53)

BCL2

an example of a proto oncogene that regulates apoptosis is...

karyotype changes

changes in the number and appearance of chromosomes. Specific changes have been identified with particular neoplasms

-karyotype changes
-balanced translocations
-deletions
-gene amplifications
-aneuploidy
-microRNAs and cancer
-epigenetics
-selective pressures

genetic lesions that lead to cancer

balanced translocations

translocation moves the gene to where its under an inappropriate, highly active protomer. Translocations make fusion proteins. Lymphocytes and their precursors are the most common types of cells where genome rearrangements occur. This is because these cells intentionally make DNA breaks in rearranging their antibody or TCR genes. This occurs in MYC and Burkitt's lymphoma and follicular B cell lymphoma and BCL2

deletions

second most common type of karyotypic abnormality. Large ones are more common in hematopoietic solid tumors. Often this occurs to tumor suppressors. Causes loss of heterozygosity, point mutation in one allele and deletion of the other.

amplifications

Extra copies of particular genes. This occurs in NMYC neuroblastoma and ERB2 breast cancer

aneuploidy

number of chromosomes that is not a multiple of normal haploid number (23). This occurs because of mitotic checkpoint errors.

MicroRNAs and Cancer

non-coding single stranded regulatory RNA. Oncogene expression is increased and tumor suppressor expression is decreased.

epigenetics

reversible, heritable changes in gene expression. This is not a mutation. Methylation of histones and DNA change expression of genes. Cancer cells have global hypomethylation of the genome and hypermethylation of certain protomers.

hypermethylation

epigenetic change that silences gene expression. Promoters of tumor suppressor genes

hypomethylation

epigenetic change that makes the genome unstable and leads to tumors in mice

selective pressures

multiple genetic alterations which result in transformed phenotype. Tumor progression, the fact that cancer becomes more malignant with time is a phenomenon that has been observed often. Initial tumor is monoclonal, but by the time cancer reaches its dangerous stage clinically, they may be very heterozygous because the tumor cells are undergoing darwinian selection. This can be immune and non-immune. Subclones that bear advantageous mutations out compete those that don't. Tumors that recur are more aggressive and more resistant to treatment

-mismatch repair
-nucleotide excision repair
-recombination repair

the three repair systems

Hereditary Nonpolyposis Colon Cancer Syndrome

problems with mismatch repair. Carcinoma of the cecum and proximal colon. Mismatch repair genes proofread DNA to make sure mismatches don't accumulate. At lease four genes are implicated. The effect is indirect, it allows mutations in genes that contribute to the hallmarks.

Xeroderma pigmentosum

mutations contribute to higher risk of sun damage from UV light. UV cross linking of pyrimidine is not repaired by the excision process (problem with nucleotide excision). Several proteins are involved, loss of one is enough to cause a problem

Fanconi anemia

problem with recombination repair. Group of autosomal recessive disorders. Phenotypes are complex and characterized by other issues too, like anemia. Also BRCA1 and BRCA2 in breast cancer, chromosomal breaks and severe aneuploidy.