16 Development, Stem Cells and Cancer

16 Development, Stem Cells and Cancer
CAMPBELL BIOLOGY IN FOCUS Urry • Cain • Wasserman • Minorsky • Reece 16 Development, Stem Cells and Cancer Kathleen Fitzpatrick and Nicole Tunbridge, Simon Fraser University Modified by James R. Jabbur, Houston Community College © 2016 Pearson Education, Inc

Overview: Orchestrating Life’s Processes
The development of a fertilized egg into an adult requires a precisely regulated program of gene expression Understanding this program has progressed mainly by studying model organisms Stem cells are key to the developmental process Orchestrating proper gene expression by all cells is crucial for life

Figure 18.1 What regulates the precise pattern of expression of different genes?

Concept 16.1: A program of differential gene expression leads to the different cell types in a multicellular organism During embryonic development, a fertilized egg gives rise to many different cell types These cell types are organized successively into tissues, organs, organ systems, and ultimately, the whole organism This developmental program is orchestrated by specific gene expression

A Genetic Program for Embryonic Development
The transformation from zygote to adult results from successive cell division, cell differentiation, and morphogenesis Cell determination and differentiation is the process by which cells become specialized in structure and function The physical processes that give an organism its shape constitute morphogenesis These processes are driven by differential gene expression, which is caused by cytoplasmic determinants and inductive signals

(b) Newly hatched tadpole
Figure 16.2 From fertilized egg to animal: what a difference four days makes 1 mm 2 mm (a) Fertilized eggs of a frog (b) Newly hatched tadpole

Cytoplasmic Determinants and Inductive Signals
An egg’s cytoplasm contains RNA, proteins, and other substances that are distributed unevenly in the unfertilized egg Cytoplasmic determinants are maternal substances in the gestating embryo that influence early development As the zygote divides by mitosis, cells contain different cytoplasmic determinants, leading to differential gene expression The other important source of developmental information is the environment around the cell, especially signals from nearby cells In the process called induction, signal molecules from embryonic cells cause transcriptional changes in nearby target cells Thus, interactions between cells induce differentiation of specialized cell types

Animation: Cell Signaling
Unfertilized egg cell Sperm Nucleus Fertilization Two different cytoplasmic determinants NUCLEUS Early embryo (32 cells) Zygote Signal transduction pathway Mitotic cell division Signal receptor Signal molecule (inducer) Two-celled embryo Figure Sources of developmental information for the early embryo (a) Cytoplasmic determinants in the egg (b) Induction by nearby cells Animation: Cell Signaling

Sequential Regulation of Gene Expression During Cellular Differentiation
Cellular determination precedes cellular differentiation, when a cell commits to its final state of specialization Cellular differentiation is marked by the production of tissue-specific proteins As an example, myoblasts produce skeletal muscle-specific proteins, forming skeletal muscle cells MyoD is one of several “master regulatory genes”; it encodes a transcription factor (protein) that binds to enhancers of various target genes, committing a cell to become skeletal muscle

(Differentiated Cell)
Nucleus Master regulatory gene myoD Other muscle-specific genes DNA Embryonic precursor cell OFF OFF (Stem Cell) mRNA OFF MyoD protein (transcription factor) Myoblast (Determined Cell) Figure Determination and differentiation of muscle cells mRNA mRNA mRNA mRNA Myosin, other muscle proteins, and cell cycle- blocking proteins MyoD Another transcription factor Skeletal Muscle fiber (Differentiated Cell)

Apoptosis: Programmed Cell Death
Apoptosis is programmed or controlled cell suicide and is important in many biological processes throughout life During apoptosis, a cell is chopped up and packaged into vesicles for digestion by scavenger cells This process also prevents dying cell contents from leaking out, damaging neighboring cells

Cells undergoing apoptosis
1 mm Interdigital tissue Cells undergoing apoptosis Space between digits Figure 16.6 Effect of apoptosis during paw development in the mouse

Apoptosis results when specific proteins that “accelerate” apoptosis (called Caspases) override those that “slow down” apoptosis The role of apoptosis was first studied in a uniquely structured soil worm, Caenorhabditis elegans (C. elegans)

Pattern Formation: Setting Up the Body Plan
Pattern formation is the development of a spatial organization of tissues and organs, and begins with the establishment of body axes Positional information, the molecular cues that control pattern formation, tells a cell its location relative to the body axes and to neighboring cells As a paradigm, pattern formation has been extensively studied in the fruit fly Drosophila melanogaster

“Bzzzzzzz”

The Life Cycle of Drosophila
In Drosophila, eggs develop in the female’s ovary, surrounded by ovarian nurse cells and follicle cells Cytoplasmic determinants in the unfertilized egg determine the axes before fertilization (also referred to as morphogens) After fertilization, the embryo develops into a segmented larva with three larval stages Eventually, the larva forms a pupa within which it metamorphoses into an adult fly The Nobel Prize was awarded for the discovery of homeotic genes, which control fly pattern formation

Development from egg to larva
Follicle cell 1 Egg cell developing within ovarian follicle Nucleus Egg cell Nurse cell 2 Unfertilized egg Egg shell Depleted nurse cells Fertilization Laying of egg 3 Fertilized egg Embryonic development Figure Key developmental events in the life cycle of Drosophila 4 Segmented embryo 0.1 mm Body segments Hatching 5 Larval stage Development from egg to larva

Head Thorax Abdomen 0.5 mm Dorsal Right BODY AXES Anterior Posterior
Figure Key developmental events in the life cycle of Drosophila Left Ventral Adult fruit fly

Animation: Development of Head-Tail Axis in Fruit Flies
Axis Establishment Maternal effect genes, including bicoid, encode for cytoplasmic determinants that initially establish the axes of the body of Drosophila These maternal effect genes are also called egg-polarity genes because they control the orientation of the egg and consequently the fly This is an example of the gradient hypothesis, in which gradients of substances called morphogens establish an embryo’s axes and other features Animation: Development of Head-Tail Axis in Fruit Flies

Mutant larva (bicoid-/-)
EXPERIMENT Tail Head T1 T2 A8 T3 A7 A1 A2 A5 A6 A3 A4 Wild-type larva Tail Tail A8 A8 A7 A6 A7 Mutant larva (bicoid-/-) RESULTS Figure Is Bicoid a morphogen that determines the anterior end of a fruit fly? Fertilization, translation of bicoid mRNA 100 µm Anterior end Bicoid mRNA in mature unfertilized egg Bicoid protein in early embryo CONCLUSION Nurse cells Egg bicoid mRNA Developing egg Bicoid mRNA in mature unfertilized egg Bicoid protein in early embryo

Concept 16.2: Cloning organisms showed that differentiated cells could be reprogrammed and ultimately led to the production of stem cells In organismal cloning, one or more organisms develop from a single cell without meiosis or fertilization The cloned individuals are genetically identical to the “parent” that donated the single cell The current interest in organismal cloning arises mainly from its potential to generate stem cells, which can be used to regenerate defective tissues in living organisms (i.e. replacing a bad liver)

“Anybody moves and the nose gets it.”
Sleeper “Anybody moves and the nose gets it.”

Cloning Plants: Single-Cell Cultures
One experimental approach for testing genomic equivalence is to see whether a differentiated cell can generate a whole organism F. C. Steward and his students first cloned whole carrot plants in the 1950s When incubated in culture medium, single differentiated cells from the root were able to grow into complete adult plants This work showed that differentiation is not necessarily irreversible Cells that can give rise to all the specialized cell types in the organism are called totipotent

EXPERIMENT RESULTS Transverse section of carrot root 2-mg fragments
Plant Cloning EXPERIMENT RESULTS Transverse section of carrot root 2-mg fragments Figure Can a differentiated plant cell develop into a whole plant? Fragments were cultured in nu- trient medium; stirring caused single cells to shear off into the liquid. Single cells free in suspension began to divide. Embryonic plant developed from a cultured single cell. Plantlet was cultured on agar medium. Later it was planted in soil. A single somatic carrot cell developed into a mature carrot plant.

Cloning Animals: Nuclear Transplantation
In the cloning of animals, the nucleus of an unfertilized egg cell or zygote is replaced with the nucleus of a differentiated cell, called nuclear transplantation Experiments with frog embryos showed that a transplanted nucleus can often support normal development of the egg However, the older the donor nucleus, the lower the percentage of normally developing tadpoles John Gurdon concluded from this work that nuclear potential is restricted as development and differentiation proceed

(totipotent stem cell) Donor nucleus transplanted
Nuclear Transplantation embryo egg cell tadpole EXPERIMENT UV Destroys DNA Fully differentiated Intestinal cell Less differentiated Embryo cell (totipotent stem cell) Donor nucleus transplanted Donor nucleus transplanted Enucleated egg cell (recipient) Egg with donor nucleus activated to begin development Figure Can the nucleus from a differentiated animal cell direct development of an organism? RESULTS Most develop into tadpoles Most stop developing before tadpole stage

Reproductive Cloning of Mammals
In 1997, Scottish researchers announced the birth of Dolly, a lamb cloned from an adult sheep by nuclear transplantation from a differentiated mammary cell Dolly’s premature death in 2003, as well as her arthritis, led to speculation that her cells were not as healthy as those of a normal sheep, possibly reflecting incomplete reprogramming of the original transplanted nucleus

Figure 16.12 Dolly, the first mammal cloned by nuclear transplantation

TECHNIQUE RESULTS Organism Cloning Mammary cell donor Egg cell donor
1 2 (Nucleus removed by aspiration) Cultured mammary cells Egg cell from ovary 3 Cells fused 3 Nucleus from mammary cell inside egg cell 4 Cell grown In culture Early embryo Implanted in uterus of a third sheep Figure Reproductive cloning of a mammal by nuclear transplantation For the Discovery Video Cloning, go to Animation and Video Files. 5 Surrogate mother 6 Embryonic development Lamb (“Dolly”) genetically identical to mammary cell donor RESULTS

Since 1997, cloning has been demonstrated in many mammals, including mice, cats, cows, horses, mules, pigs and dogs CC (for Carbon Copy) was the first cloned cat However, CC differed somewhat from her female “parent” – the behavior of the two cats is very different!

Figure 20.19 CC, the first cloned cat, and her single parent

Problems Associated with Animal Cloning
In most nuclear transplantation studies, only a small percentage of cloned embryos have developed normally to birth Many epigenetic changes, such as acetylation of histones or methylation of DNA, must be reversed in the nucleus from a donor animal in order for genes to be expressed or repressed appropriately for early stages of development (therein lay the problem, oh young Skywalker)

Stem Cells of Animals A stem cell is a relatively unspecialized cell that can reproduce itself indefinitely and differentiate into specialized cells of one or more types

Embryonic and Adult Stem Cells
Stem cells isolated from early embryos at the blastocyst stage are called embryonic stem cells (ES cells) These cells are able to differentiate into all cell types (totipotent) The adult body also has partially differentiated adult stem cells (pluripotent), which replace non-reproducing specialized cells The aim of stem cell research is to supply cells for the repair of damaged or diseased organs

Cells generating all embryonic cell types
Stem Cell types Embryonic stem cells Adult stem cells Early human embryo at blastocyst stage (mammalian equiva- lent of blastula) From bone marrow in this example Cells generating all embryonic cell types Cells generating some cell types Cultured stem cells Different culture conditions (direct differentiation) Figure Working with stem cells Liver cells Nerve cells Blood cells Different types of differentiated cells

Induced Pluripotent Stem Cells (iPS Cells)
Researchers are able to “deprogram” fully differentiated cells to act like ES cells using retroviruses Cells transformed this way are called induced pluripotent stem cells – iPS Cells (Gurdon and Yamanaka received the Nobel Prize in 2012) Cells of patients suffering from certain diseases can be reprogrammed, becoming iPS cells for use in studying the disease and enacting potential treatments In the field of regenerative medicine, a patient’s own cells might be reprogrammed into iPS cells to potentially replace nonfunctional (diseased) cells

Four “stem cell” master regulatory genes introduced
Stem Cell Induction Stem cell Precursor cell Skin fibroblast cell Oct3/4 Sox2 Four “stem cell” master regulatory genes introduced Figure Inquiry: Can a fully differentiated human cell be “deprogrammed” to become a stem cell? c-Myc Klf4 Induced pluripotent stem (iPS) cell

Concept 16.3: Abnormal regulation of genes that affect the cell cycle can lead to Cancer
The gene regulation systems that go wrong during cancer are the very same systems involved in embryonic development Cancer can be caused by mutations to genes that regulate cell growth, apoptosis and chromosomal stability [explain: think of it as a gas pedal, brake pedal and engine kill switch] Tumor viruses can also cause cancer by facilitating the overexpression of tumor causing genes

Types of Genes Associated with Cancer: Oncogenes and Proto-Oncogenes
Proto-oncogenes are normal cellular genes that are responsible for normal cell growth and division Oncogenes are mutated proto-oncogenes; they lose their “normal” functional character Conversion of a proto-oncogene to an oncogene can lead to an abnormal stimulation of the cell cycle (next slide)

Proto-oncogenes can be converted to oncogenes by:
DNA Translocation or transposition: Gene amplification: Point mutation: within a control element within the gene New promoter Oncogene Oncogene Figure Genetic changes that can turn proto-oncogenes into oncogenes Normal growth- stimulating protein in excess Normal growth-stimulating protein in excess Normal growth- stimulating protein in excess Hyperactive or degradation- resistant protein

Ras One example of a cell cycle stimulating pathway- a “gas” pedal 1
Growth factor 1 MUTATION Ras Hyperactive Ras protein (product of oncogene) issues signals on its own Ras 3 G protein GTP Ras GTP 2 Receptor 4 Protein kinases (phosphorylation cascade) NUCLEUS 5 Transcription factor (activator) DNA Figure Signaling pathways that regulate cell division Gene expression Protein that stimulates the cell cycle One example of a cell cycle stimulating pathway- a “gas” pedal

Tumor-Suppressor Genes
Tumor-suppressor genes encode proteins that help prevent uncontrolled cell growth Mutations that decrease protein products of tumor-suppressor genes contribute to the onset of cancer Tumor-suppressor proteins Repair damaged DNA Control cell adhesion Inhibit the cell cycle in the cell-signaling pathway

p53 One example of a cell cycle inhibiting pathway – a “brake” pedal 2
Protein kinases MUTATION Defective or missing transcription factor, such as p53, cannot activate 3 Active form of p53 UV light 1 DNA damage in genome DNA Figure Signaling pathways that regulate cell division Protein that inhibits the cell cycle One example of a cell cycle inhibiting pathway – a “brake” pedal

Interference with Normal Cell-Signaling Pathways
Mutations in the ras proto-oncogene, the p53 tumor-suppressor gene and telomerase are common in human cancers Mutations in the ras gene can lead to production of a hyperactive Ras protein and increased cell division, thus increased growth Mutations in the p53 gene prevent suppression of the cell cycle. Suppression of the cell cycle is important in the case of damage to a cell’s DNA; p53 prevents a cell from passing on mutations due to DNA damage Mutations in telomerase expression maintain chromosomal integrity, causing the genome to become immortal

Cancer is caused by three failed systems
EFFECTS OF MUTATIONS Ras – oncoprotein overexpressed p53 – tumor suppressor absent Cell cycle overstimulated Increased cell division Cell cycle not inhibited Figure Signaling pathways that regulate cell division Telomerase – chromosomal maintainence abnormally expressed Genome Immortality

The Multistep Model of Cancer Development
Since mutation always takes place during our lifetime, the incidence of cancer increases with age Thus, the development of cancer is a multistep process, beginning with an innocuous growth that develops into a benign one and ultimately, metastasizes throughout the body Colon Loss of tumor- suppressor gene APC (or other) 1 Activation of ras oncogene 2 Loss of tumor-suppressor gene p53 4 Colon wall Loss of tumor-suppressor gene DCC 3 Additional mutations 5 Normal colon epithelial cells Small benign growth (polyp) Larger benign growth (adenoma) Malignant tumor (carcinoma)

Case study: breast cancer as a therapeutic model
Breast cancer is the second most common form of cancer in the United States and the most common form among women In 2012, the Cancer Genome Atlas Network published results of a genomics approach to profiling types of breast cancer Four major types were identified based on their molecular signatures © 2016 Pearson Education, Inc. 49

MAKE CONNECTIONS: Genomics, Cell Signaling and Cancer
Luminal A Luminal B Basal-like ERa PR • ERa • PR • HER2 • ERa++ • 15–20% of breast cancers • ERa+++ • PR++ • More aggressive; poorer prognosis than other subtypes • PR++ • HER2 (shown here); some HER2++ • HER2- • 40% of breast cancers • 15–20% of breast cancers • Best prognosis • Poorer prognosis than luminal A subtype A research scientist examines DNA sequencing data from breast cancer samples. HER2 HER2 • ERa Normal Breast Cells in a Milk Duct • PR In a normal breast cell, the three signal receptors are at normal levels (indicated by +): • HER2++ HER2 receptor • 10–15% of breast cancers • ERa+ Duct interior Dimer • Poorer prognosis than luminal • PR+ • HER2+ A subtype Estrogen receptor alpha (ERa) Milk duct Figure Make connections: genomics, cell signaling, and cancer Signaling molecule Progesterone receptor (PR) P P P P Response (cell division) ATP ADP P P HER2 receptor Mammary gland lobule Epithelial milk-secreting cell Epithelial milk-secreting cell Treatment with Herceptin for the HER2 subtype Herceptin molecule Support cell Extracellular matrix HER2 receptors

MAKE CONNECTIONS: Genomics, Cell Signaling and Cancer
Figure Make connections: genomics, cell signaling, and cancer (part 1) A research scientist examines DNA sequencing data from breast cancer Samples – this is called “profiling”

Normal Breast Cells in a Milk Duct
In a normal breast cell, the three signal receptors are at normal levels (indicated by +): • ERa+ Duct interior • PR+ Estrogen receptor alpha (ERa) • HER2+ Milk duct Progesterone receptor (PR) HER2 receptor Mammary gland lobule Figure Make connections: genomics, cell signaling, and cancer (part 2) Epithelial milk-secreting cell Epithelial milk-secreting cell Support cell Extracellular matrix

• Poorer prognosis than luminal A subtype
HER2 HER2 • ERa • PR • HER2++ • 10–15% of breast cancers • Poorer prognosis than luminal A subtype Signaling molecule HER2 receptor Dimer P P Response (cell division) P P P P ATP ADP Figure Make connections: genomics, cell signaling, and cancer (part 4) Treatment with Herceptin for the HER2 subtype Herceptin molecule HER2 receptors

Inherited Predisposition and Other Factors Contributing to Cancer
Individuals can inherit oncogenes or mutant alleles of tumor-suppressor genes Inherited mutations in the tumor-suppressor gene adenomatous polyposis coli (APC) are common in individuals with colorectal cancer Mutations in the BRCA1 or BRCA2 gene are found in at least half of inherited breast cancers, and tests using DNA sequencing can detect these mutations DNA breakage can contribute to cancer, thus the risk of cancer can be lowered by minimizing exposure to agents that damage DNA, such as ultraviolet radiation and chemicals found in cigarette smoke Also, viruses play a role in about 15% of human cancers by donating an oncogene to a cell, disrupting a tumor-suppressor gene, or converting a proto-oncogene into an oncogene

Protein processing and degradation
Chromatin modification Transcription • Genes in highly compacted chromatin are generally not transcribed. • Regulation of transcription initiation: DNA control elements bind specific transcription factors. • Histone acetylation seems to loosen chromatin structure, enhancing transcription. Bending of the DNA enables activators to contact proteins at the promoter, initiating transcription. • DNA methylation generally reduces transcription. • Coordinate regulation: Enhancer for liver-specific genes Enhancer for lens-specific genes Chromatin modification Transcription RNA processing • Alternative RNA splicing: RNA processing Primary RNA transcript mRNA degradation Translation mRNA or Fig. 18-UN4 Protein processing and degradation Translation • Initiation of translation can be controlled via regulation of initiation factors. mRNA degradation • Each mRNA has a characteristic life span, determined in part by sequences in the 5 and 3 UTRs. Protein processing and degradation • Protein processing and degradation by proteasomes are subject to regulation.

Chromatin modification
• Small RNAs can promote the formation of heterochromatin in certain regions, blocking transcription. Chromatin modification Transcription Translation RNA processing • miRNA or siRNA can block the translation of specific mRNAs. mRNA degradation Translation Protein processing and degradation Fig. 18-UN5 mRNA degradation • miRNA or siRNA can target specific mRNAs for destruction.

Figure 11.19 Apoptosis of human white blood cells

(inhibits Ced-4 activity)
Active Ced-9 protein (inhibits Ced-4 activity) Mitochondrion Ced-4 Ced-3 Receptor for death- signaling molecule Inactive proteins No Death signal Cell forms blebs Inactive Ced-9 protein Death- signaling molecule Figure Molecular basis of apoptosis in C. elegans Active Ced-4 Active Ced-3 Proteases Nucleases Activation cascade Death signal

Precursor cell (determined lineage)
Stem cell Cell division Stem cell and Precursor cell (determined lineage) Figure How stem cells maintain their own population and generate differentiated cells (determined lineage) Fat cells OR Bone cells OR White blood cells

Milk duct Mammary Epithelial gland milk-secreting cell lobule Support
Figure a Make connections: genomics, cell signaling, and cancer (part 2a) Mammary gland lobule Epithelial milk-secreting cell Support cell

Figure 16.21-2b Normal Breast Cells in a Milk Duct
In a normal breast cell, the three signal receptors are at normal levels (indicated by +): • ERa+ Duct interior • PR+ Estrogen receptor alpha (ERa) • HER2+ Support cell Progesterone receptor (PR) Figure b Make connections: genomics, cell signaling, and cancer (part 2b) HER2 receptor Extracellular matrix

MAKE CONNECTIONS: Genomics, Cell Signaling, and Cancer
Luminal A Luminal B Basal-like ERa PR • ERa • ERa+++ • ERa++ • PR • PR++ • PR++ • HER2 • HER2 • HER2 (shown here); some HER2++ • 15–20% of breast cancers • 40% of breast cancers • More aggressive; poorer prognosis than other subtypes • Best prognosis • 15–20% of breast cancers • Poorer prognosis than luminal A subtype HER2 HER2 Figure Make connections: genomics, cell signaling, and cancer (part 3) • ERa • PR • HER2++ • 10–15% of breast cancers • Poorer prognosis than luminal A subtype

• HER2 (shown here); some HER2++ • 40% of breast cancers
Luminal A Luminal B ERa PR • ERa+++ • ERa++ • PR+ • PR++ Figure a Make connections: genomics, cell signaling, and cancer (part 3a) • HER2 • HER2 (shown here); some HER2++ • 40% of breast cancers • 15–20% of breast cancers • Best prognosis • Poorer prognosis than luminal A subtype

• More aggressive; poorer prognosis than other subtypes
Basal-like HER2 HER2 • ERa • ERa • PR • PR • HER2 • HER2++ Figure b Make connections: genomics, cell signaling, and cancer (part 3b) • 15–20% of breast cancers • 10–15% of breast cancers • More aggressive; poorer prognosis than other subtypes • Poorer prognosis than luminal A subtype

Figure 16.21-4a HER2 © 2016 Pearson Education, Inc. Signaling molecule
receptor Dimer Figure a Make connections: genomics, cell signaling, and cancer (part 4a) P P Response (cell division) P P P P ATP ADP © 2016 Pearson Education, Inc.

Figure 16.21-4b Treatment with Herceptin for the HER2 subtype
molecule HER2 receptors Figure b Make connections: genomics, cell signaling, and cancer (part 4b) © 2016 Pearson Education, Inc.

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