Carcinogenesis Flashcards
What is cancer?
Cancer is the general name for a group of diseases characterized by uncontrolled cellular growth
- Neoplasia: the growth of new tissue
- Neoplasm/tumor: an abnormal growth of tissue forming a mass
- Transformation: process of converting a normal cell into a cell having attributes of a cancer cell
Normal vs transformed cells
Transformed cells have attributes of cancer cells
NORMAL CELLS
- cell proliferation: controlled
- number of cell divisions: limited, 50 cell cycles (Hayflick limit), mortal
- contact inhibition: yes, monolayer culture
- dependent on growth factors: yes
- tumor formation: no
TRANSFORMED CELL
- cell proliferation: uncontrolled
- number of cell divisions: unlimited (immortal)
- contact inhibition: no, multilayer culture
- dependent on growth factors: no
- tumor formation: yes, tumorigenic in laboratory animals
Immprtalization: process whereby a cell normally having limited replicative potential acquires the ability to multiply indefinitely
Major classifications of malignant tumors
- Epithelial tissue: carcinoma (squamous epithelial carcinoma, adenocarcinoma)
- non-epithelial tissue: Sarcoma (connective and supporting tissue -> e.g. fibrosarcoma, liposarcoma), Leukemia, lymphoma (hematopoietic), neuroectodermal tumors (e.g. glioma, neuroblastoma)
- other tumors (do not fit to the major classification): melanoma, small-cell lung carcinoma
Carcinomas are responsible for more than 80 % of the cancer-related deaths in the Western countries.
Tumor dignity: Benign or malignant
Benign tumors
* Local growth without invading adjacent tissues
* Often harmless to their hosts
* In some cases, complications through
(1) “Mass effect”
- obstruct passage ways
- press on nerves
- disrupt the function of vital organs etc.
(2) Hormone overproduction
- e.g. thyroid adenoma
physical & mental symptoms (depression, apathy, weight loss,
weakness, heart arrhythmia, etc.)
(3) Malignant transformation
(colorectal adenoma (polyp) -> adenocarcinoma
Malignant tumors
* Infiltration of nearby tissues
* Production of metastases
* Metastases are responsible for more than 90% of deaths
- hepatic metastasis -> liver failure
- pulmonary metastasis-> lung failure etc.
Other complications, e.g.:
* Obstruction of the colon, bile duct, etc.
*Cancer cachexia (loss of weight, atrophy of muscle and fatty tissue, etc.)
Staging of cancer
Obligatory parameters
* TNM staging system (Tumor, Nodes, Metastases)
- Description of the size of the primary tumor and the extension of spreading (tissue infiltration)
- Involvement of lymph nodes
- Spreading to distant organs (metastasis)
- Grading
- Determination of cell anaplasia (loss of differentiation) in tumor tissue
in comparison to the normal tissue - Degree of tumor aggressiveness
- Variability in size, shape and staining of cells and their nuclei
- Nucleus (↑) to cytoplasm (↓) ratio - Mitotic activity (↑)
- Atypical mitoses (↑)
Other parameters
* Measurement of serum tumor markers (LDH, alpha-fetoprotein, PSA)
* Completeness of the operation (resection-boundaries free of cancer cells or not)
Aims: help to plan treatment and give an indication of prognosis
Risk factors
Factors that increase the probability to develop cancer
Risk factors (increased probability for a disease)
-> parental inheritance (predisposition) (5-10%)
-> environmental factors (90-95%) <-> genetic constitution (genotype)
The percentage contribution of genetic factors and environmental factors toward cancer risk.
Environmental risk factors
(1) Lifestyle
- nutrition (20-40%), tobacco use (25-30%), alcohol (3%), obesity, physical activity, etc.
(2) Naturally occurring exposures - ultraviolet light, radon gas
- infectious agents, predominantly viruses (5%) (e.g. HCV, EBV, HPV)
(3) Medical treatment
- chemotherapy, radiation, and immune system-suppressing
drugs used after organ transplants, etc.
(4) Air pollution (2%)
- car exhaust gases, industrial emission
(5) Workplace exposures (4-8%*)
Carcinoma in situ (CIS)
- locally limited primary tumor
- intact basement membrane
- no invasion/infiltration into adjacent tissue
Cervical cancer as example for tumor progression
Hyperplasia (CIN 1)
* Thickened epithelium
* Basal cells with increased mitosis rate (purple cells)
* Shift of the nucleus (↑) - cytoplasm (↓) ratio
Dysplasia (CIN 2)
* Mitoses now also in the intermediate layer
* Morphological changes visible
Carcinoma in situ (CIN 3)
* All cell layers contain immature, polymorphic, proliferating cells
Cervical carcinoma
* Infiltration/Invasion (Basal membrane is broken through)
* Metastasis
Clonal expansion and selection
Normal cells:
1st mutation in one cell
➢Proliferative and/or survival advandage
Pre-cancerous:
Progeny of the mutant cell dominate over cells lacking this mutation
➢1st clonal expansion
2nd mutation results in a double mutated cell ➢Greater proliferative
and/or survival advantage
Carcinoma:
Progeny of the double mutated cell dominate over single mutated cells
➢2nd clonal expansion
… and so forth
Clonal expansion of tumors
monoclonal tumors:
* Only one cell becomes cancerous
* All of the cells in the tumor are descendants of that cell
polygonal tumors:
* Individual cells become cancerous
* The tumor represents the descendants of these original cells
X-inactivation pattern
early embryo -> X-inactivation -> adult tissue
Marker to measure the clonality of tumor cell populations:
* Inactivated X chromosome in human female cells
X-inactivation
* Early embryogenesis (during formation of the blastocyst)
* Random X-inactivation in each cell (m, maternal; p, paternal)
* Causing
- transcriptional silencing of almost all of the genes (~900)
- condensation of this chromosome (Barr body)
* Descendants of a cell: inactivation of the same X chromosome
* Formation of cell patches (clones) in the adult female body
Mp: inactive paternal X
mP: inactive maternal X
The Barr body is visible in the interphase nuclei, where it remains condensed & associated with the nuclear membrane
X-linked G6PD
- X-linked marker: glucose-6-phosphate dehydrogenase (G6PD)
- some human females are heterozygous for G6PD (mosaic)
- the two allelic forms of G6PD show different heat sensitivity
Enzyme-histochemistry of heated tissue from a heterozygous female (section of intestine)
Dark spots: heat-resistant isoform, active enzyme
Light grey spot: heat-sensitive isoform, inactive enzyme
-> Normal tissue contains both type A and B of G6PD
-> tumours contain either type A and B of the G6PD, never both
- The two allelic isoforms of G6PD differ in their gel electrophoretic mobility
-> the tumor cells originate from a single cell (monoclonal)
Monoclonality in multiple myelomas
Healthy person
* Immunoglobulins (Ig) migrate as heterogeneous collection (smear), they are polyclonal
Multiple myeloma patient
(malignant plasma cells secreting Igs)
* The heterogeneous population of Ig molecules is replaced by a single antibody species (M-spike)
* Myeloma cells secret the same form of Igs, because they are monoclonal (monoclonal gammopathy)
-> Most – if not all – human cancers appear to be monoclonal
Intra-tumor heterogeneity
During tumor progression, cells in the tumor mass become heterogeneous
monoclonal tumor cell -> tumor progression -> heterogenous cell population
Intra-tumor heterogeneity:
1. genetic level (different mutations, epigenetic changes, chromosomal instability)
2. morphological level (e.g. cell size, nucleus size, marker proteins)
3. functional level (proliferation rate, tumorigenic potential)
Intra-tumor heterogeneity in high-grade non-small-cell lung cancer.
- Numbers of chromosomes fluctuate strongly from cell to cell (chromosomes 11 and 17)
- presence of polyploid nuclei in some cells
- different cell size
