Chapter 25 Cancer & Chapter 22 Stem Cells, genome editing

all our tissues arise from 3 embryonic layers: true or false

true

what are these 3 embryonic layers

1. endoderm

2. mesoderm

3. ectoderm

describes cells that have unlimited capability (all types of tissues in organism)

totipotent stem cells

describes cells are capable of giving rise to most, but not all, tissues of an organism

pluripotent stem cells

describe cells that are committed to give rise to cells that have specific function

multipotent stem cells

how can you get stem cells in adulthood

1. take from blastocyst

2. iPSCs

where are embryonic stem cells (ES) derived from

inner cell mass (ICM) of blastocysts

what is alternative for obtaining stem cells from blastocyst/embryo

reprograming

process of reverting mature, specialized cells into induced pluripotent stem cells (iPSCs)

what does reprogramming mean

differentiation of stem cell derivatives can be ‘steered’ by what

exposing them to appropiate soluble factors in vitro

somatic cell nuclear transfer

SCNT

any non-sex cell in the body

somatic cell

before advent of iPS cells, what would be done?

nuclei from adult tissues could be used for cloning

1. reproductive

2. therapeutic

2 types of cloning

1. remove cell from male, remove DNA from unfertlized egg

2. fuse cells

3. create early embryo culture

4. implant in surrogate

reproductive cloning using somatic cell nuclear transfer

method of genome editing

CRISPR/ Cas 9

clustered regularly interspaced short palindromic repeats

CRISPR

where was Cas9 first identified

in bacteria and archaea

large group of diseases in which abnormal cells divide without control and can invade nearby tissues

cancer

what do cancer cells change

range from point mutations and gene deletions and amplification to whole chromosome gain/loss

complex organs composed of different cell types that interact with their environment to obtain a maximal growth advantage

tumors

acquire migratory properties that enable them to invade the surrounding tissues

• spread through the body to establish secondary sites of growth

metastatic tumor cells

constraint to a single mass

benign

invasive and metastatic

malignant

____ ____ abnormal growth of tissues (tumors) is cancerous

not all

normal cells divide when new cells are needed and refrain from dividing when they are not

basic rule of cellular social behaviors

normal cells live if they are needed and ___ when it is required to ____

die

normal cells are good neighbors, they maintain their differentiated character, occupy their proper place (in space and time) and do not stray away into other territories or neighborhoods

third rule of cellular social behaviors

invade and colonize territories normally reserved for other cells (invasion and metastasis)

cancer cells proliferate in defiance of the normal constrains and …

1. alterations in cell proliferation

2. akternations in DNA damage response

3. alterations in cell growth

4. alterations in cell survival

ways to create cancers

carinomas originate from what

epithelial tissue origin

where do sarcomas originate from

connective tissue origin

hematopoietic malignancies originate from

blood-forming tissues

• bone marrow, lymph nodes, lymphatic system

neuro-ectodermal malignancies originate from

neuroectoderm (embryonic layer that gives rise to central and peripheral nervous system)

where are therapies more successful?

hematopoietic site

cancer is a genetic disease meaning …

it results from an accumulation of somatic mutations

• enhance ability to proliferate, survive or both

what causes cancer

1. mutagens

2. spontaneous errors in DNA replication and repair

agents that can cause changes in DNA sequence

mutagens

human papillomavirus uses what two viral proteins to sequester the host cell’s p53 and Rb respectively

E6 and E7

detector of DNA damage

what does p53 do

halt cells at restriction point

what does Rb do

what works synergistically to contribute to cancer development and progression

oncogenic genes

1. dominant gain of function mutations in proto-oncogenes

2. recessive loss-of-function mutations in tumor-suppressor genes

what types of mutations contribute to cancer

mutation in one copy of proto-oncogene creates

oncogene

• gene that can give you cancer

• excessive cell survival, proliferation or both

what does oncogene do

tumor-supressor genes ____ cell division

inhibit

what does “mutation inactivates one copy of tumor supressor gene” do

no effect of mutation in one gene copy

what does “second mutation inactivates second gene copy” do

complete loss of tumor suppressor gene activity

what causes cancer in dominant way

oncogenes

oncogenes

what arise from normal cellular genes (proto-oncogenes) or are introduced by virus

oncogenes code for …

abnormal forms or excessive quantities of such proteins

oncogenes stimulate …

excessive cell proliferation and/or promote cell survival

how can proto-oncogenes be activated to oncogenes

1. mutation in coding sequence

2. gene amplification

3. chromosome rearrangement

what does mutation in coding sequence create

hyperactive mutant protein made in normal amounts

what does gene amplification make

normal protein overproduced

what does chromosome rearrangement make

1. nearby regulatory gene sequence causes normal protein to be overproduced

2. fusion with actively transcribed gene produces hyperactive fusion protein

in all cases of proto-oncogene activation to oncogene there is an increase in gene function: true or false

true

what does tumor suppressor gene do

mutation inactivates one copy of tumor suppressor gene

genes whose total inactivation can lead to cancer

tumor suppressor gene

what is normal function of tumor suppressor gene

restrain proliferation

restrict pasage from G1 to S

RB gene (tumor suppressor)

prevents cells with damaged DNA from poliferating

p53 gene (tumor suppressor)

inhibits Wnt pathway by degrading beta-catenin

APC

two genetic mechanisms underlying retinoblastoma

1. hereditary retinoblastoma

2. sporadic retinoblastoma

loss of functional Rb allele, gives rise to tumors in retina

what does hereditary retinoblastoma do

loss of functional Rb allele, doesn’t do anything, leading to…

loss of functional 2nd functional Rb allele, homozygous cell gives rise to tumors in retina

what does sporadic retinoblastoma do

what is one of the most frequently dystregulated pathways in human cancers

P13K-AKT-mTOR signaling pathway

how does loss of p53 lead to chromosomal instability

because the mutant survives and proliferates→ creating massive chromosomal damage→ cell death OR chromosomes are particially stabilized and cell survives with MANY mutations

invasion of surrounding tissue

metastasis

what causes metastasis

• decreased cell-cell adhesion

  • E-cadherin is lost

• increased motility

• secretion of proteases that degrade extracellular matrix and basal lamina

metastatic cancer cells use…

invadopodium to penetrate basement membrane and migrate to distant sites in body

2/3 of metastases have to do with

blood flow patterns (lungs and liver)

1/3 of metastases result from

“seed and soil” hypothesis

metastatic cells are carried to many organs but only few have optimal growth environment

“seed and soil” hypothesis

growth of blood vessels

angiogenesis

angiogensis

what do tumors promote

how do tumors promote angiogensis

they secrete VEGF

1. surgery

2. radiation

3. chemo

4. angiogenesis inhibitors

5. bone marrow transplant

6. rational drug design

7. immunotherapy

   1. CAR therapy

cancer treatments include

what is PCM (precision cancer medicine)

concept in which oncologists increasingly strive to tailor the use of targeted therapies in order to match complexity of cancer genome

1. t cell taken from blood

2. identify cancer specific antigen

3. create CAR sequence

4. put information back into t cell

5. amplify CAR t cell

6. give to patient by infusion

CAR (chimeric antigen receptor) therapy