Cancer IV-V: stem cells Flashcards

Question

medicinal MSCs can secrete molecules that establish what?

Answer 1

Other secreted molecules establish a regenerative microenvironment by establishing a powerful trophic field Medicinal MSCs play a key role in creating a "trophic field"—a supportive environment that facilitates tissue repair and regeneration regenerative microenvironment - anti-apoptotic - anti-scarring - angiogenic - mitotic

Answer 2

pericytes pericyte --> MSC --> activated MSC --> medicinal MSC

Answer 3

pluripotent stem cells associated with blood vessels and are found throughout the body

Answer 4

can differentiate into all types of adult cells belonging to a particular group (ie. hematopoietic stem cells) Multipotency: a type of “restricted potential” stem cell that can only differentiate into a single family of cells

Answer 5

hematopoietic stem cells (HSCs) → HSCs CANNOT differentiate into brain or cardiac (heart) cells but can differentiate into many types of blood cells

Answer 6

can only differentiate into ONE type of adult cell (ie. spermatogonium)

Answer 7

totipotent: fertilized egg, embryonic stem cells pluripotent: mesenchymal stem cells, adipose stem cells multipotent: hematopoietic stem cells unipotent: spermatogonium

Answer 8

The equation calculates the probability of cancer (p) with 5 parameters: number of cell divisions (d) number of stem cells (N*m) number of critical rate limiting pathway driver mutations (k) mutation rate (u) In this model, progression to cancer STARTS AT CONCEPTION (aka at birth) and mutations accumulate with cell division Transformation (aka fully fledged or clinically relevant cancer) occurs when a critical number of rate limiting pathway mutations first accumulates within a single STEM cell

Answer 9

Means that we all have cancer cells growing in us → relates back to the MIT lecture quote: “everybody in this room who does not die of something else first WILL die of CANCER” (aka we all have cancer but 2/3 or 3/4 of us will die of something else first)

Answer 10

regeneration aka divided stem cells constantly help to repair and rebuild our bodies to keep us healthy

Answer 11

a type of adult stem cell found in skeletal muscle that play a crucial role in muscle regeneration and repair They are a form of muscle stem cell that is activated in response to muscle injury or stress, helping to regenerate and repair damaged muscle tissue

Answer 12

Muscles continuously regenerate → muscle tissue is completely replaced every 15 years or so (as long as the satellite progenitor cells are not depleted)

Answer 13

The cold war enabled measurement of a cell’s lifetime

Answer 14

Above ground weapons testing led to a spike in atmospheric Carbon (isotope 14) which labeled the DNA of anyone alive at the time People undergoing rapid growth during these years had up to 2% of their biomolecules (ie. DNA) labeled with 14C

Answer 15

Cerebellum neurons: < or = lifetime Occipital-cortex neurons: younger than cerebellum neurons Jejunum non-epithelial: 10.7 years Skeletal muscle: 15.1 years

Answer 16

Cerebellum neurons Occipital-cortex neurons Jejunum non-epithelial Skeletal muscle liver!

Answer 17

revival The varying regenerative properties of amphibian, reptile, and mammal tails result from differences in neural stem cells found in the animals’ spinal cords

Answer 18

Tissue engineering: the creation of new tissues or organs in the lab to replace diseased, worn out, or injured body parts Requirements for tissue engineering: Cells of the correct type Biomaterials / scaffold Control of cell fate

Answer 19

Tissue engineering exploits stem cells for regeneration

Answer 20

stem cells can be derived from differentiated cells Embryonic stem cells? → NO because there are ethical issues involved in using ES cells Adult stem cells → NO because they are difficult to obtain (with the exception of fat, but even so, the donor-host immune matching is problematic)

Answer 21

normal/healthy stem cells (despite contributing to cancer risk) are NOT cancer stem cells (CSCs) AND not all cancer cells are CSCs

Answer 22

DEFY the principle of clonal succession (a more highly differentiated cell becomes LESS differentiated) - can generate stem cells from differentiated cells and use these differentiated cells to make mature tissue Possess all of the hallmarks of cancer/rate-limiting hits (aka has ALL of the properties needed to rapidly regenerate the tumor) Are relatively SLOW growing (due to the metabolic burden of expressing additional genes) Are drug resistant

Answer 23

not all cells in a tumor need to express VEGF (angiogenesis supplies all cells with blood) not all cells in a tumor need to express PD-L1 (the cells that do express PD-L1 can inactivate the “killer” T cells and thus protect non expressing cells) key point: individual cells in a tumor may NOT have all the “hallmarks of cancer” but CSC presumably DO have all the hallmarks

Answer 24

An observation from in vitro cell culture experiments where CSCs divide for example, once a week instead of once a day CSCs needs to express additional genes (ie. VEGF, PD-L1): the expression of these genes presumably comes at the expense of faster replication ^^ Note: the key word is relatively: if the CSCs can divide once a week in the body like they do in cell culture, it can take only a few months instead of 60-70 years

Answer 25

1. Conventional therapies target RAPIDLY growing cells --> killing the majority of cells in a tumor which often leads to clinical remission 2. CSCs disproportionately avoid eradication and rapidly regenerate the tumor (often within months) instead of 50-70 years

Answer 26

future cancer therapies are proposed to target the CSCs 1. Drugs with less toxicity can be developed to selectively target the CSCs 2. Without CSCs and their ability to regenerate the tumor, it will safely and harmlessly “melt away” over time

Answer 27

Induced pluripotent stem cells (aka iPSCs): terminally differentiated cells that have been converted into pluripotent stem cells via transfection of Oct-¾ SOX2, c-Myc, and Klf4 genes researchers can convert terminally differentiated stem cells into pluripotent stem cells HOWEVER, researchers have not been able to generate totipotent stem cells yet

Answer 28

Oct-¾, SOX2, c-Myc, Klf4

Answer 29

iPSC technology application 1: disease models - The “disease in a dish” model can be used to study genetic diseases when patient samples are not available (ie. for muscle or neurological disorders) - Best of all, this application is safe to use RIGHT NOW iPSC technology application 2: replacement cells/tissues - iPSCs hold tremendous potential of cell and tissue-based regenerative therapies - HOWEVER, safety is a significant concern for iPSC therapies

Answer 30

CANCER iPSCs and cancer: risk from the reprogramming factors

Answer 31

iPSC reprogramming factors ARE cancer genes

Answer 32

recall Hallmark 8: metabolic reprogramming → however as shown below, MYC actually does much more than metabolic reprogramming in cancer

Answer 33

Oct3/4: important during embryonic development and for the maintenance of CSCs

Answer 34

also promotes cancer develop and contributes to several hallmarks of cancer

Answer 35

Klf4: a “two faced” molecule that can be a tumor suppressor (left) but can also participate in cancer stem cell maintenance (right)

Answer 36

a genetic disorder where the immune system is severely weakened or absent → leaves individuals highly vulnerable to infections and is caused by mutations in genes that are essential for the development and function of T cells and B cells

Answer 37

An early gene therapy test in the late 1990s cured most children (8/10 in one study) In the next few years, a high number (4/9 patients in one study) of children developed a specific type of leukemia During gene therapy, the IL2RG gene which was needed to cure SCID integrated into part of the genome that regulated the LOM2 gene and activated this cancer gene

Answer 38

Genes needed for iPSC induction were integrated into the host cell’s genome Advantage: long term expression for the genes required for iPSC creation Disadvantage: integration potentially can activate cancer genes (ie. LMO2)

Answer 39

Used non-integrative DNA which was safer but inefficient Integration of the gene into the host cell's genome does not occur → INCREASED SAFETY however the tradeoff is that gene expression is transient (for a small amount of time) which DECREASED EFFICIENCY

Answer 40

VEGF turned off after angiogenesis is complete PD-L1 turned off (except for macrophages and dendritic cells) Telomerase turned off (expect in rapidly dividing progenitor cells) iPSC reprogramming factors turned off in fully differentiated cells

Answer 41

EPIGENETICS turn genes off and then turned them back on in cancer

Answer 42

NO! → bottom line: gain of function hits almost never are genetic! instead they are epigenetic ie. gain-of-function cancer gene: VEGF, telomerase, PD-L1

Answer 43

it could be waiting until a gain of function hit kicks in: ie. gain of VEGF for angiogenesis, telomerase to confer immortality, or PDL-1 to avoid immunesurveillance

Answer 44

the changes caused by the modification of GENE EXPRESSION rather than by direct alteration of the genetic code (DNA) `

Answer 45

During development and oncogenesis, many genes are turned on → after development, many genes are turned off ie. Genes like VEGF and telomerase need to be turned on during early development, but then these genes are turned off in an adult and then turned back on in cancer Summary: during development, cancer genes are imprinted (turned off) through a long and complicated process but they CAN be turned back on through epigenetic regulation in cancer and iPSC production These enzymes and other involved proteins include the iPSC reprogramming factors!

Answer 46

Gain of function hits → cancer is an EPIGENETIC disease ^^ This idea was developed by Johns Hopkins BME Andy Feinberg

Answer 47

Imprinted genes (genes that are turned off) are linked to DNA methylation - Imprinted genes are regulated by DNA methylation, which silences one allele (either the maternal or paternal copy) - The addition of methyl groups to cytosines in promoter regions of genes results in gene inactivation DNMTs methylate DNA → certain cytosines are methylated → specifically, DNA methylation in promoter regions of genes results in inactivation

Answer 48

genes where only one allele (either the maternal or paternal copy) of the gene is active, while the other is silenced This selective silencing is an example of epigenetic regulation, where the gene expression is controlled by mechanisms like DNA methylation and histone modifications

Answer 49

hit: a mutation that inactivates a proto-oncogene to create a cancer gene: ie. Rb, p53 This is a genetic effect (aka a direct change in the DNA sequence) → HOWEVER in other cases, a genetic explanation doesn’t make sense Consider: what if any gain of function cancer gene (ie. VEGF, telomerase, PD-L1) suffers a genetic hit (aka experiences a mutation) ^^ bottom line: gain of function hits almost never are genetic! --> instead they are epigenetic