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Samenvatting Molecular Biology of the Cell, ISBN: 9780815344322 Cellulaire Oncologie (5052CEO12Y)
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Samenvatting Cellulaire OncologieHC 1 The nature of Cancer
Tumors arise from normal tissues
- Tumors are created by malfunctioning cells that cannot maintain tissues of normal
form and function.
- Tumors bear certain histological features that resemble those of normal tissue of
their origin (histopathology).
Benign vs malignant tumors
- Tumors that grow locally without invading adjacent tissues are classified as benign
(large majority).
- Benign tumors may nevertheless cause problems:
o Thyroid adenomas (pre-malignant epithelial growths) may cause excessive
release of thyroid hormone into the circulation, leading to hyperthyroidism.
o Pituitary adenomas may release growth hormones into the circulation,
causing excessive growth of certain tissues ® a condition known as
acromegaly.
- Tumors that invade nearby tissues and spawn metastases are termed malignant.
o Metastases are responsible for most deaths from cancer. Metastases zitten
vol met melanine (Daarom zijn ze zwart van kleur).
Tumors arise from many specialized cell types:
Ø The majority of human tumors arise from epithelial tissues.
o Epithelia ® sheets of cells that line the walls of cavities and channels or cover
the body (skin). Weefsels die het lumen van organen bedekken.
o Basement membrane (basal lamina/ netwerk van eiwitten) is made of
extracellular matrix (ECM) and separates the epithelial cells from the
underlying layer of supportive connective tissue cells (stroma).
Ø Epithelia give rise to the most common human cancers ® the carcinomas
o Include tumors of the gastrointernal tract (mouth; esophagus; stomach and
small & large intestines); skin; mammary gland; pancreas; lung; liver; ovary;
uterus; prostate; gallbladder and urinary bladder.
There are 2 major types of epithelial-origin cancers:
1. Cells forming protective cell layers in the epithelium give rise to squamous cell
carcinomas.
2. Specialized cells that secrete substances into the ducts or cavities that they line
generate adenocarcinomas. (Cellen die heel veel eiwitten exporteren)
Non-epithelial cancers:
1. connective tissue ® sarcomas
- Derive from fibroblasts and related collagen-secreting cells, adipocytes (store fat in
their cytoplasm), osteoblasts (form bones), myocytes (form muscles). Allemaal
mesenchymal cell type.
2. Hematopoietic tissues (blood forming)
- Precursors of erythrocytes (Red blood cells), antibody-secreting (plasma) cells, T and
B lymphocytes.
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, - Leukemia (“white blood”): spawned by malignant non-pigmented hematopoietic
cells, moving freely through the circulation (excl. red blood cells).
- Lymphomas are malignant B or T lymphocytes that aggregate and form solid tumors,
usually found in lymph nodes.
3. Originating from nervous system
- Examples include gliomas, glioblastomas, neuroblastomas, schwannomas and
medulloblastomas.
Not all tumors can be easily classified:
- Melanomas derive from melanocytes (pigmented cells of the skin and retina, which
themselves originate from nervous system).
- Small-cell lung carcinomas (SCLCs) contain neurosecretory-like cells (such as cells of
the adrenal glands which secrete biologically active peptides). SCLCs may originate in
endodermal cell populations of the lung that have shed some of their epithelial
characteristics and taken on those of a neural lineage.
- Some tumors (and normal cells) undergo transdifferentiation (move from one
differentiation lineage or phenotype to another)
o At the borders of mane carcinomas, epithelial cancer cells often change shape
and gene expression programs that resemble nearby stromal cells. This is
termed the epithelial-mesenchymal transition (EMT).
- Teratomas (usually benign) arise from germ cell (egg and sperm) precursors that
persist at inappropriate sites in the developing fetus, retaining the ability to generate
most tissues. The cells in different sectors of common teratomas create adult-like
tissues.
- Teratomas are genetically wild type (no mutations).
- 2-4% of tumors shed virtually all tissue-specificity (Dedifferentiation) and the tumors
are anaplastic ®it is no longer possible to identify the tissues from which they have
arisen.
Cancers develop progressively
- Cancer cell populations evolve progressively toward greater degrees of
aggressive/invasive behavior in a multi-step process.
- Hyperplastic growth ® excessive number of cells, which nevertheless retain the
ability to assemble into tissues that appear reasonably normal. (Lumen wordt veel
Kleiner).
- Metaplastic growth ® normally present tissue is replaced by cells from a nearby
tissue.
- Dysplasia ® translational state between benign and malignant growth:
o Variability in nuclear size and shape, increased staining, increased ratio of
nuclear versus cytoplasmic size, increased mitotic activity, lack of normal
cytoplasmic features.
o Aberrant relative numbers of the various cell types.
o Major effects on the overall tissue architecture.
- Adenomas, polyps, papilloma’s and skin warts contain all cell types of normal
epithelial tissue but are greatly expanded.
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, o Usually grow to a certain size and then stop, respecting the boundary of the
basement membrane and do not invade underlying tissues. Considered to be
benign.
- Neoplasm ® invasion into the underlying tissues (e.g., carcinoma cells which break
through the basement membrane and invade into the adjacent stroma).
Ø But tumor progression (normal ® hyperplastic ® dysplastic ® neoplastic ®
metastatic) is only suggestive and not universal.
Are tumors monoclonal?
Ø Tumors are monoclonal
o Myelomas are derived from the B-cell precursors of antibody-producing
plasma cells.
o Normally, the pool of these precursors consists of millions of subpopulations
expressing its own specific antibody.
o But all myeloma cells in a patient produce identical antibody. This indicates
their descent from a single, common ancestor.
o Often, all tumor cells carry a particular chromosome rearrangement or
mutation.
§ This also indicates their descent from a single, common ancestor, in
which the event happened.
Cancer’s exhibit altered energy metabolism
Ø Normal cells in aerobic conditions use glycolysis in the cytosol to break down glucose
into pyruvate, which is then broken down in mitochondria into CO2 (in citric acid
cycle (Krebs cycle)).
Warburg Effect:
Ø Under anaerobic/ hypoxic conditions cells use glycolysis ® reduce pyruvate to
lactate and secrete lactate.
Ø Many types of cancer cells use glycolysis, even when exposed to sufficient oxygen.
Why Warburg effect?
Ø Krebs cycle provides 32 ATP molecules vs only 2 molecules from glycolysis. But:
1. Cancers are often oxygen deprived.
2. Intermediates generated during glycolysis can be used in biosynthesis.
- Cancer cells overexpress glucose transporters (e.g., GLUT1). Accumulation of
radiolabeled glucose injected into a patient’s vascular system can be used to detect
tumors.
- Normal cells use more than 30% of their imported glucose to make ATP, while cancer
cells use only 1%.
Two obvious contributing factors to cancer:
1. Heredity
2. Environment
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, HC 2 Viruses, oncogenes, and growth factors
Cancer and Viruses
Foci ® loss of contact inhibition.
Viruses can transform infected cells in culture
- Permissive hosts (allowing virus replication).
o Host cells quickly killed by the virus. Hier krijg je geen kanker van omdat het
virus de cel heel snel doodt.
- Non-permissive hosts (not allowing virus replication)
o Transformed cells (at low frequency).
Some viruses build their DNA into the host genome
Ø Exploiting replication machinery of the host.
o 99% of cervical carcinomas carry integrated fragments of HPV genomes.
Some viruses persist episomally (outside of host genome)
- Some viral proteins bridge viral genomes and cellular chromatin.
- Viral genomes “hitchhike” with cellular chromosomes during mitosis.
Some RNA viruses (retroviruses) use reverse transcription to integrate their genetic material
into DNA of the host cell.
- RSV is an example of a retrovirus.
- This is a normal and required step in their life cycle (different than in the case of DNA
viruses, which do not have to integrate).
Some viruses kidnap and exploit their host genes
Ø Existing genes could be oncogenic.
Ø A single gene was sufficient for oncogenic transformations.
Ø Viruses can be used as vectors to deliver foreign DNA into cells.
Proto-oncogene= genen die van zichzelf voor geen transformatie kunnen zorgen maar onder
bepaalde omstandigheden wel.
C-src zorgt voor cel-proliferatie. Sommige virussen hebben een C-src gen (RSV).
Many oncogenic retroviruses act like RSV
- Most kidnapped genes are silent, but some are oncogenic
- Oncogenic viruses provide an ‘accidental’ glimpse at proto-oncogenes.
Slowly transforming viruses do not carry proto-oncogenes
- Activate proto-oncogenes by insertional mutagenesis (inserting their genomes
nearby).
Ø Bepaalde stukken van het viraal genoom worden in onhandige plekken van de host
genome ingevoegd. Een virale promotor komt net voor een gen met een milde
promotor te staan ® het gevolg hiervan is dat er te veel van het eiwit wordt
geproduceerd waardoor bepaalde processen in disbalans komen.
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