1. Termin Flashcards
Tip cell formation
Tip cell = Endothelial cells that spearhead the vascular sprouts
- characterized by position, long and dynamic filopodia and migratory behavior
- VEGF activates tip cell migration
- respond to attractive and repulsive directional signals presented by the environment and thereby define the route in which the new sprout grows
- reuquired to create new connections between different sprouts to generate an interconnected and functional vascular network
- Tip cells express VEGFR2/3 together with several co-receptors (neuropilin-1 (NRP1))
- Tip cell attraction by VEGF gradients
- Upon activation: Tip cells express DLL4, that binds to Notch receptors on follower stalk cell
Receiver operating characteristics
- Graphical plot that illustrates the diagnostic ability of a binary classier system as its discrimination threshold is varied
- to draw a ROC curve, only the true positive rate (TP) and false positive rate (FP) are needed
- Best possible prediction method would yield a point in the upper left corner or a coordinate (0,1) of the ROC space, representing 100% sensitivity (no false negatives) and 100% specificity (no false positives)
- points above the line of no discrimination represent good classification results (better than random); points below the line represent bad results (worse than random)
Validity
Analytical validity is a measure of how well the test measures what it’s supposed to measure (a test designed to detect a mutation associated with melanoma should not give a positive result for an unrelated mutation associated with diabetes)
Specificity
- ability to correctly identify patients without cancer
- a specific test gives a positive result only the the cancer is present
-> no false positives
Sensitivity
- ability to correctly identify patients with cancer
- a sensitive test correctly identifies everyone who has the cancer
-> no false negatives
Staging of cancer -> TNM staging system
Tumor, Nodes, Metastasis
- Description of the size of the primary tumor and the extension of spreading (tissue infiltration)
- involvement of lymph nodes
- spreading to distant organs (metastasis)
Staging of cancer -> Grading
- Determination of cells anaplasia (loss of differentiation) in tumor tissue in comparison to the normal tissue
- degree of tumor aggressiveness
- Pathology: Variability in size, shape and staining of cells and their nuclei
- nucleus (high) and cytoplasm (low) ration
- Mytotic activity (high)
- Atypical mitoses (high)
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
There are four grading categories with an additional one where the grade cannot be assessed
Tumors with highly abnormal cell appearance and large numbers of dividing cells
- tend to grow more quickly
- spread to other organs more frequently (metastasis)
- less responsive to therapy than cancers whose cells have a more normal appearance
-> poor prognosis
Stem cell niche
- is a specialized microenvironment that protects stem cells and regulates their behavior
Example: C. elegans germline stem cell niche: one cell, the mesenchymal distal tip cell, provides a niche for germline stem cells - the stem cell niche can act on a stem cell by various mechanisms:
-> Direct contact: direct contact between the stem cell and the niche cells
-> Soluble factors: releasing of soluble factors by the niche
-> Intermediate cell: Intermediate cells “communicate” between the niche and the stem cell
Pre-metastatic niche
- Hypoxia
- ROS level increased
-> both up regulate CSC stress signaling pathways - in the case of hijacking of a normal stem cell niche: CSCs up regulate EMT pathway in the surrounding non tumorigenic cells and transform them into CSCs to further support the CSCs to colonize the new niche
- secreted soluble factors are key players in bone marrow cell mobilization during metastasis
- membrane vesicles derived from both tumor and host cells
Pre-metastatic niche formation
Tumors metastasize to particular organs due to the migration of hematopoietic bone marrow cells expressing VEGFR1 and stromab cells to these particular sites poor to the formation of clinically relevant metastasis.
- influenced by many different bodily processes, including the suppression of the immune system and an increase in the presence of cytokines and other growth factors as well as extracellular matrix deposition and remodeling
- Hypoxia in the primary tumor and the movement of exosomes from the primary tumor to the secondary organ are additional phenomena that are partially responsible for the formation of pre-metastatic niches
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
Transformed cell
- Cell proliferation: uncontrolled
- number of cell divisions: unlimited (immortal)
- contact inhibition: no, multilayer cell culture
- dependent on growth factors: no
- tumor formation: yes, tumorigenic in laboratory animals
Immortalization: process whereby a cell normally having limited replicative potential acquires the ability to multiply indefinitely
Cancer stem cell characteristics
Fraction with a small number of cells
- behave like stem cells
- self-renewal
- unlimited proliferative potential
- production of a large number of progeny which are in different state of differentiation (different surface markers) and with limited proliferative potential
Therapeutic challenge of cancer stem cells
Radio- and chemotherapy resistance due to “stemless” inductions:
- Drug export: elevated expression and high activity of ABC transporters
- ROS decrease: High ALDH activity
- High survival: Anti-apoptotic molecules, high telomerase activity, DNA damage
- Quiescence
Six hallmarks of (malignant) cancer
1) Self-suffiency in growth signals -> Activate H-Ras oncogene
2) Insensitivty to anti-growth signals -> Lose retinoblastoma suppressor
3) Evading apoptosis -> produce IGF survival factors
4) Limitless replicative potential -> turn on telomerase
5) Sustained angiogenesis -> produce VEGF inducer
6) Tissue invasion & metastasis -> inactivate E-cadherin
-> The hallmarks of cancer are thought to be necessarily acquired during the multistep pathogenesis pathways leading to most forms of human cancer
-> certain forms of cancer may be less dependent on one hallmark or another
7) Emerging Hallmarks
-> Avoiding immune destruction
-> Deregulation cellular energetics
8) Enabling characteristics
-> genome instability and mutation
-> Tumor-promoting inflammation
Loss of heterozygosity
- Typically, cells possess two functional alleles of a given tumor suppressor gene
- the first hit may be an inactivating mutation or the silencing of the gene by promoter hypermethylation
- the second hit may involve the loss of the second allele (LOH) or a process similar to the first hit
- if the first hit happened in the germ line or during early development, the organism will have an increased tumor risk
-> bezeichnet den Verlust der normalen Funktion des Alles eines Gens in einer Zelle, in der das andere Allel bereits inaktiviert war
-> Beispiel: Retinoblastom (Tumor in der Netzhaut des Auges): Hier wird ein Defekt an einem Chromosom vererbt, wobei der Defekt erst dann zu einer Tumorbildung führen kann, wenn das zweite Gen durch externe Faktoren (wie chemische Karzinogene oder auch Strahlung) ebenfalls mutiert
Natural endogenous DNA damages -> DNA alkylation
- endogenous and chemical
- O6-MG is an alkylation of the oxygen atom of guanine and highly mutagenic
- 1 of 8 unprepared O6-MG damages is leading to a mutation > high cancer risk
- Repaired by O6-methylguanine-DNA methyltransferase (MGMT)
- MGMT is a suicide enzyme (1 MGMT protein can repair 1 damage)
DNA damage -> Synthesis -> MGMT -> Transfer of Methyl group -> Degradation
Oncogenes vs Tumor suppressor genes
Proto-oncogenes: code for proteins that stimulate the cell cycle and promote cell growth and proliferation
Tumor suppressor genes: code for proteins that repress cell cycle progression and promote apoptosis
-> oncogenes result from the activation (turning on) of photo-oncogenes
-> tumor suppressor genes cause cancer when the are inactivated (turned off)
Tumor suppressor genes
Functions:
1) Repression of genes that are essential for counting the progression of the cell cycle
2) Coupling the cell cycle to DNA damage
3) If damage cannot be repaired, the cell should initiate apoptosis
4) Proteins that function in DNA repair, preventing cells from replicating mutations
5) Some proteins involved in cell adhesion prevent tumor cells from dispersing, block loss of contact inhibition and inhibit metastasis
Some examples
pRb (retinoblastoma) -> proliferation
APC (colorectal cancer) -> proliferation
p53 (many tumors) -> Division, apoptosis
BRCA1 (breast cancer) -> DNA repair
Tumor supressor genes -> Gatekeeper
Genes that directly hinder cell division or promote cell differentiation or cell death
- Mutations lead to the appearance of unregulated dividing cells (e.g. pRB in Retinoblastoma)