Molecular Oncology Flashcards
1
Q
Definition Tumor
A
- Tumor [DE= Schwellung]
- Tumors originate from neoplastically transformed cells
- Tumors consist of tumor cells, immune cells and other cell types
- Clinically relevant: the space used by the tumor (DE: Raumforderung)
2
Q
Formen von Tumoren
A
- Sarcoma : tumors of the connective tissue
- carcinoma : tumors of the epithelia
- Leukemia : tumors of the hematopoietic system
- Lymphoma : tumors of the hematopoietic system
- Tumors of the central nervous system : glioma, gliosarcoma, and others
- Tumors of the peripheral nervous system: Schwannoma, Neurofibroma
- Melanoma: tumors derived from the pigment cells
3
Q
Aging and effects
A
- During life time the cells of an organism begin to age. This may lead to:
- Mutations of oncogenes and tumor suppressor genes -> frequent causes of cancer.
- Dysfunction of telomeres -> several diseases, including cancer.
- dysfunction of repair -> several diseases, including cancer.
- loss of chromosomes and/or changes on the chromatin level -> several diseases, including cancer.
- The capacity to generate functional progenitors and effector cells is reduced.
- Aging of adNSC/adNPC may lead to the accumulation of damages, which are then inherited to the daughter cells.
- The stem cell niche is important as well (affects cell division; regulation of mitosis; „homing“).
4
Q
Aging and senescence
A
- Aging involves several molecular/physiological changes, including shortening of the telomeres.
- Ultimately, the cells will show “senescence”: Induction of senescence may be triggered by ROS or other effectors from the (micro-) environment.
- In some cases, inactivation of tumor suppressor genes overcomes “senescence”: -> proliferation
- This re-entry in proliferation is associated with telomere stabilization/re-activation of telomerase.
- Senescence may be observed in vivo and in vitro (i.e. cell culture systems).
- Senescence in cell cultures may be induced by different parameters, including e.g. “ROS” (reactive oxygen species), “serum deprivation” or simply “progressive passaging”.
- Senescent cancer cells maintain the senescent state by autocrine mechanisms and are influenced by the microenvironment. Paracrine signaling by immune cells has a cancer promoting effect.
5
Q
Difference between tumor cells and normal cells
A
major differences concern:
(1) indefinite growth and replicative immortality,
(2) deregulation of cellular energetics,
(3) evasion of growth suppressors and apoptosis,
(4) genome instability,
(5) promotion of angiogenesis and inflammation.
6
Q
Driver mutations and founder cells
A
- The primary tumor develops from a founder cell.
- The founder cell displays mutations that led to neoplastic transformations.
- More mutations and epigenetic changes are acquired later on, leading to tumor progression and eventually metastasis.
- The founder cell acquired mutations that led to neoplastic transformations.
- These mutations are referred to as “driver mutations”.
- driver mutations accumulate during early stages of tumorigenesis and provide a benefit to the tumor; they occur in “driver genes”.
- not all mutations in a driver gene are supporting cancer.
- Driver mutations lead to a severe dysfunction of the encoded protein.
- Passenger mutations do not provide a benefit to the tumor per se.
- Abundant founder mutations in colon cancer concern the K-RAS proto-oncogenes, APC and Tp53.
- Application of standard radio-/chemotherapy will induce additional mutations. These mutations may erase tumor cell populations.
- A minority of tumor cells may, however, may benefit of the mutations.
7
Q
Tumor classification
A
- Different classification systems exist and are used in clinical settings.
- The tumor classification by the WHO is most often used.
- Specific classification criteria were defined for each tumor entity.
- The suffix “-blastoma” is used to imply a tumor of primitive, incompletely differentiated (or precursor) cells, i.e. refers to
the fact that the tumor is composed of cells resembling precursor cells. - Classification is based on histopathological features. Parameters used in classification include mitotic rate, the Ki67 index, invasiveness, aneuploidy, vascularization and necrosis
- Genetic and epigenetic studies highlighted specific features of tumor entities and subtype of tumors of the same entity.
- Novel grading systems include data obtained by genome, proteome and transcriptome analyses.
- After a tumor is initiated, several factors support or stimulate growth (promotion). Hormones may act as tumor promoters.
- Benign and malignant tumors show several characteristics: e.g. malignant tumors display a increased growth rates, vascularization, necrosis and ulceration. Individual tumor cells disseminate from the primary malignant tumor and form metastasis in a secondary site.
8
Q
Factors that contribute to carcinogenesis are
A
- age, environment and life style
- Free radicals from environment; ROS („reactive oxygen species”) contribute to the various stages of tumorigenesis
- When mitochondria age, the ROS levels are increased; moreover, DNA damage repair is impaired
- shortening of Telomeres is observed during aging.
- Susceptibility: mutations present in the genome are e.g. inherited.
- tumor initiation: requires compounds which deregulate oncogenes/tumor suppressor genes.
- tumor progression: drives progression of already existing tumor cells.
9
Q
Tumorigenesis
A
- Neoplastic transformation converts a normal cell into a “tumor initiating” cell.
- Mutations occur after the cells has been exposed to carcinogens.
- Carcinogenic agents include certain chemicals (e.g. polycyclic aromatic hydrocarbons), high energy beams (X-ray, UV) but also a
subgroup of RNA and DNA viruses. - Tumor promotion may be exerted by many different agents, including hormones and phorbolesters.
- Tumor progression is often associated with genetic and epigenetic changes;
- chronic inflammation and immune evasion are important parameters
- the production of onco-metabolites and the so-called “metabolic switch” are crucial.
- In some rare cases, tumors may be transmitted between animals of the same species (e.g. Tasmanian devil).
10
Q
Tumorigenesis and the “two hit model”
A
- The development of a tumor is a multi-step process, which involves many distinct mutations.
- Several models suggest, that oncogenic “drivers” need to be established during early tumorigenesis. Later on, the functional inactivation of tumor suppressors occurs. Cell cycle, apoptosis and senescence pathways become deregulated.
- Inflammatory processes and epigenetic regulation of additional genes contribute to tumor development.
- Crucial events are the activation of the oncogenic potential of one or more proto-oncogene(s).
- Additional crucial events are the functional inactivation of one or more tumor-suppressor(s).
- In most cases, both alleles of a given tumor suppressor gene are mutated in cancer cells (by e.g.: point mutations, small or large deletions, translocations, promoter deregulation).
11
Q
The types of “hits”
A
- The mutational “hits” may be LOFs (loss of function) or GOFs (gain of function mutation).
- In addition one entire allele (or chromosome) may be lost, which is referred to as “loss of heterozygosity” (LOH).
- Epigenetic changes may lead to repression of tumor suppressor genes (e.g. promoter hypermethylation). – E.g.: BRCA1 and BRCA2;
- Mutations in promoters may lead to drastically impaired levels of tumor suppressors (e.g. BRAC1).
- BRAC1 is important for maintenance of genomic integrity. BRCA1 mutations contribute to breast and ovarian cancer.
Mutations in the BRCA1 promoter may inactivate the gene. - Epigenetic changes may also lead to de-repression of oncogenes (e.g. promoter de-methylation).
- Oncogenic drivers are acting in signaling cascades (e.g. EGFR/HER1, ErbB2/HER2, PDGFR, RAS, RAF).
12
Q
Oncogenic signaling pathways
A
Several proteins are acting together in signaling cascades (modules). The deregulation of the signaling cascades may happen at any point. However, crucial mutations have been identified by the TCGA initiative (included: genome, transcriptome and proteome analyses - and more). Similar signaling cascades are important for distinct tumors, however, the relative importance of individual factors and the type of mutation differ.
- RTK/MAP: Receptor tyrosine kinase deregulation (RTK overexpression; RTK GOFs), deregulation of RAS (GOF) and RAF (GOF)
- Pi3K/AKT/mTOR: Deregulation of the kinases Pi3K (GOF) and AKT (GOF). Functional loss of the phosphatase PTEN (LOF, LOH)
- Wnt/beta-catenin: Deregulated Wnt signaling involves mutated APC (LOF) and deregulated GSK3b (LOF, GOF) and b-catenin (GOF).
- Cell cycle: Controlled cell cycle progression by E2F is impaired or lost due to (i) overexpression of e.g. CDK4/6 or E2F, (ii) mutant pRB (LOF), and/or (iii) mutations in the CDKN2A locus (LOF of p16-INK4A) or (iv) loss of the CDKN2A locus (LOH).
- Myc transcription factors: Myc transcription factors are downstream of RTKs and Wnt signaling. GOFs of cMyc and N-Myc contribute to cancer initiation and the metabolic switch in tumors.
13
Q
Oncogenic activation
A
- Several cellular genes (proto-oncogenes) may be converted into oncogenes (c-oncs).
- Typically, these genes encode regulators of proliferation, cell survival, evasion of growth control and apoptosis.
- The c-oncs encode mitogen or cytokine receptors (e.g. receptor tyrosine kinase EGFR/HER1, HER2, PDGFR), components of signaling cascades (e.g. RAS, PTEN), kinases in signaling cascades (e.g. RAF, Pi3K, AKT, JAK2) or transcriptions factors (e.g. cMyc).
- The activation of the oncogenic potential of proto-oncogenes can occur by/after:
- retroviral transduction (e.g. c-erbB[=HER1]; v-SRC)
- single point mutations (e.g. HER2, JAK2)
- multiple mutations and/or small deletions (e.g. RAS)
- amplification of gene copy numbers (e.g. EGFR/HER1, PDGFR)
- translocation and fusion to a gene, which alters protein function (e.g. t(9;22) BCR-Abl)
- translocation under the control of a highly active promoter (e.g. t(8;14) immune globulin promoter/cMyc).
- demethylation of promoters (formerly repressed c-onc genes are activated thereafter)
14
Q
Proto-oncogenes - Some effects
A
- overactive HER1/EGFR, HER2 or PDGFR support proliferation and cell survival (via MAPK or Pi3K/AKT/mTor cascades)
- Dysfunctional RAS and RAF affect MAPK signaling.
- BCR-Abl drives proliferation and cell survival (via several oncogenic cascades)
- Overactive cMyc augments proliferation and cell survival, and impacts on metabolic pathways.
15
Q
Tumor suppressors
A
- Several proteins may act as tumor suppressors.
- In general, both alleles encoding a tumor suppressor are lost/inactive in tumor cells.
- Several tumor suppressors regulate cell cycle progression:
- (1) pRB [Retinoblastoma gene product] and p16-INK4a;
- (2) Tp53 and p14-ARF.
- Note: p16-INK4A and p14-ARF are encoded by the CDKN2A locus
- The inactivation of tumor suppressors can occur by/after:
- point mutations (e.g. pRB, Tp53; PTEN)
- mutations and/or small deletions (e.g. pRB, Tp53; PTEN)
- loss of heterozygocity (e.g. pRB, Tp53; CDKN2A locus; PTEN) - hyper-methylation of promoters (e.g. BRCA1; CDKN2A locus) - mutations in the promoter (e.g. BRCA1)
16
Q
Specific features of Tp53
A
- Tp53 is a transcription factor, which binds as a tetramer to responsive elements in Tp53 target genes.
- Target genes encode: (i) MDM2, (ii) the cell cycle inhibitor p21, (iii) repair proteins, and (iv) some pro-apoptotic proteins.
- Frequent Tp53 mutations include LOFs and GOFs. Mono-allelic LOFs may exert a dominant negative effect.
- Tp53 GOFs display new functions and are oncogenic. Tp53 GOFs contribute to proliferation and survival, genomic instability, invasiveness, migration and metastasis, immune evasion, angiogenesis and a so-called “metabolic switch”.
17
Q
Tumor micro-environment (TME)
A
- The TME impacts on tumor initiation. tumor progression, tumor maintenance, tumor recurrence and metastasis
- the TME includes: stromal composition, cell-cell interaction, cell-matrix interactions, abnormal physiology, molecular heterogeneity and cellular heterogeneity.
- Tumor cells interact with “host tissue molecules” and the host immune system impacts on tumor growth and immune evasion. The interaction is bidirectional and referred to as tumor-host interaction.
- Neoplastically transformed cells will only generate a tumor in an abnormal micro-environment. This includes non-tumor cells and an abnormal ECM (extracellular matrix), which becomes disorganized and promotes cellular transformation.
- When a tumor grows, the production of new vessels (blood and/or lymphatic vessels) is necessary. Vessels are important for access to oxygen and nutrients, but also metastasis. Release of VEGF by tumor cells supports (lymph-)angiogenesis.
- Hormonal signaling contributes to tumor growth (e.g. tumor promotion by steroid hormones). Hormone therapy may blocks abnormal hormonal signaling in cancer. However, endocrine signaling pathways and micro-environmental cues may promote hormone-resistance and lead to hormone-resistant, aggressive phenotypes.
- Metabolic alterations in tumor stroma occur early and influence the adjacent tumor cells. Metabolites secreted by tumor and non-tumor cells affect tumor growth and progression. Glucose, Tryptophan and Arginine are crucial components.
- The glycosylation pattern of tumor cells is abnormal. It impacts on malignant transformation, cellular growth and migration.
- Several non-tumor cells are present in the TME. This includes cancer-associated fibroblasts (CAFs), myofibroblasts, endothelial cells, adipocytes, mesenchymal stem cells, and various types of immune cells (e.g. cancer-associated macrophages (MAFs).
- In particular, CAFs and MAFs have a major influence on tumor growth and tumor progression.
18
Q
Adaptions, CAFS and the aging tumor micro-environment (TME)
A
- Cells and other components in the TME may show aged phenotypes and undergo senescence. This impacts on tumor initiation, progression, maintenance and relapse.
- One crucial aspect is the tumor cell plasticity: I.e. tumor cells adapt to changes in the TME and undergo genetic, epigenetic, and phenotypic changes throughout tumorigenesis. TME and cancer therapies may select for tumor cells with rare-preexisting genetic phenotypes. Together, these processes increase intratumoral heterogeneity (ITH).
- Adaptations caused by epigenetic alterations may be counteracted by inhibitors of chromatin modifying enzymes.
- Fibroblasts support cellular and microenvironmental homeostasis via regulated secretion of cytokines, chemokines and other signaling proteins. In young, healthy tissues the fibroblast secretome provides a growth-restrictive micro-environment for premalignant cells.
- Fibroblasts undergo a short-lived senescence-associated secretory phenotype (SASP); SASP fibroblasts are quickly cleared by the body in young tissue. In aged tissue SASP fibroblasts accumulate and establish a tumor-permissive, chronic inflammatory micro-environment.
- In addition, Fibroblasts regulate tissue structure via extracellular matrix (ECM) deposition
- SASP fibroblasts promote extensive ECM remodeling. Thereby, they increase tumorigenesis, invasion of tumor cells and immune cell trafficking.
19
Q
Extracellular Matrix
A
- ECM: Components of the ECM (e.g. integrins) serve as ligands for cell surface receptors and provide extrinsic cues that can alter a cells phenotype. Elastic ECM is observed in brain, lung and breast, stiffer ECM structures are seen in skin and bone.
- ECM integrity and elastic properties decrease when an organism ages; ECM stiffness is increased in aged tissue.
- ECM dysregulation is associated with tumor progression and metastasis in hard and soft tissue. Increased crosslinking and stiffening of the ECM will promote tumor progression.
- Age-induced accumulation of SASP is a key mechanism in induction of ECM stiffness in site-specific niches, which may ultimately allow increased tumorigenesis and tumor cell dissemination.
20
Q
Cancer stem cells
A
- The TME displays a cellular heterogeneity. This includes the presence of various non-cancer cells (CAFs, MAFs, MSCs, adipocytes, endothelial cells etc. – see previous summaries). In addition, clones of cancer cells exist in the TME.
- A major role in tumor progression and relapse is ascribed to cancer cells with similarities to stem cells: these cancer cells express a subset of pluripotency factors and display indefinite self-renewal. Hence they are referred to as cancer stem cells (CSCs.)
- CSCs are neoplastically transformed cells, which make up only a small proportion of the tumor mass, but sustain tumor growth.
- CSCs contain the driver mutations that initiated neoplastic transformation. In addition, the CSCs accumulate further mutations and
epigenetic changes. Hence, CSCs with genetic and epi-genetic differences may be present in the same tumor. - Positive and negative selection by the tumor micro-environment will act on the various CSCs present in a given tumor.
- Only a subfraction of the CSCs is able to disseminate from the primary tumor. These CSCs undergo EMT (epithelial-mesenchymal transition) and enter the blood stream. Having reached a suitable new location the CSCs undergo MET to occupy the metastatic niche. EMT and MET are regulated by factors present in the tumor micro-environment.
- Several models address the origin of CSCs:
- (i) CSCs might be derivatives of somatic stem cells, which accumulated mutations and underwent neoplastic transformation. In this scenario, the cells were already stem cells when neoplastic transformation occurred.
- (ii) CSCs might be derivatives of somatic progenitors, which accumulated mutations and underwent neoplastic transformation. In this case, the cells had to switch on genes that augmented the degree of stemness.
- (iii) CSCs might originate from terminally differentiated, mature cells, which underwent neoplastic transformation and were converted into stem cells. In this case, the cells had to re-activate genes that mediate stemness.
21
Q
micro-RNAs and cancer
A
Synthesis and processing of miRNAs are affected in cancer:
- Micro-RNAs are synthesized as a precursor, the pri-miRNA.
- The pri-miRNA is processed to pre-miRNA by DROSHA and DGCR8, both of which might be mutated in cancer cells.
- The pre-miRNA is exported into the cytoplasm by Exportin 5, which is also mutated in same cancers.
- Further processing of the pre-miRNA in the cytoplasm is by DICER and TRBP.
- Finally the miRNA duplex is converted into the single-stranded mature mi-RNA and loaded in the RISC complex.
- Mutations in the genes encoding DICER, TRBP and the Argonaute protein AGO2, respectively, have been observed in cancer cells.
- Together this observations highlight the importance of miRNA for cancer. miRNAs interfere with normal function of proto-oncogenes and tumor suppressor genes.
- The let-7 miRNA cluster affects the proto-oncogenes c-myc and ras, as well as the genes coding for DICER1 and CDK6.
- Moreover, the let-7 miRNA cluster impacts on stemness, modulating the stemness state of cancer stem cells.
- The mRNAs coding for the transcription factor E2F and the tumor suppressor PTEN are affected by the miRNAs.
- Notably, several miRNAs interfere with the stability of the PTEN mRNA: these include miR.221/222.
miRNAs affect chemo-resistance and are therefore crucial in anti-cancer trials:
- miRNAs which increase chemo-resistance include the miR.221/222.
- miRNAs which decrease chemo-resistance include the let-7 miRNAs.
- Hence, several miRNAs may be useful in anti-cancer therapies, whereas other miRNAs will interfere with a beneficial therapy outcome.
22
Q
Cancer Metabolism
A
- Cancer metabolism is abnormal. This includes carbohydrate, amino acid and lipid metabolism.
- Cancer cells undergo a metabolic switch, which includes several strategies and affects several metabolic pathways.
- On the one hand, the changes represent a metabolic adaptation of the tumor cells to changes in the tumor micro-environment (TME). On the other hand, tumor cell metabolism impacts on the TME (e.g. changes in pH due to release of large amounts of lactate) and promotes genomic instability and epigenetic changes.
- Non-tumor cells in the TME supply metabolites (direct release of metabolites or release in form of exosomes) to the neighboring tumor cells – and vice versa. Also, tumor cells supply metabolites to other tumor cells.
- The metabolic adaptations include bioenergetics [ATP production by glycolysis and/or OXPHOS], biosynthesis [activation of pathways synthesizing or metabolizing carbohydrates, nucleotides, lipids, or amino acids] and adaptations of the redox- balance [NAD(P)+/NAD(P)H, ROS].
23
Q
Metabolism in the tumor micro-environment
A
- One major cause for metabolic adaptation/metabolic switch is the reduced or low oxygen (hypoxia) content in the TME. Only in close proximity of the blood vessels, the concentrations of oxygen and nutrients are high. Hypoxia contributes to therapy resistance, vascularization, metastasis and epithelial-mesenchymal transition (EMT). Moreover, Hypoxia stabilizes the transcription factor HIF1a, which would be hydroxylated and subsequently poly-ubiquitinated and degraded under normoxic conditions. HIF1a is one major player in metabolic adaptation, the other is c-Myc. Both transcription factors co- operate in up-regulation of transporters (GLUT, MCT1,4), but have opposite effects in adjusting mitochondrial activity.
- HIF1a up-regulates glucose uptake, lactate release and most glycolytic enzymes (directly or via up-regulation of miRNAs). At the same time entry of pyruvate in the citric acid cycle (TCA) is prevented and OXPHOS is shut-down. This is mediated by the inhibition of the PDH (pyruvate dehydrogenase) complex with help of the kinase PDK1, which is activated by HIF1a.
24
Q
Aerobic glycolysis and Warburg effect; role of fat
A
- Otto Warburg discovered that cancer cells produce energy predominantly by glycolysis; this happens in hypoxic TME (anaerobic glycolysis), but also in presence of O2 (aerobic glycolysis). The phenomenon is referred to as “Warburg effect”. Warburg linked mitochondrial respiratory defects in cancer cells to aerobic glycolysis. It remains to be clarified, if the Warburg effect plays a causal role in cancers or if it is an epiphenomenon in tumorigenesis.
- In tumor cells, the pyruvate produced by glycolysis is further converted to lactate. This overcomes glycolysis-mediated NAD+ depletion in anaerobic tumor cells. In tumor cells with aerobic glycolysis (lactagenic cancer cells) excessive lactate production is a key element of the metabolic switch (i.e. the dysregulation of glucose and lactate metabolism).
- Lactate may leave the cell or is transported into the mitochondria. Both is mediated by monocarboxylate transporters [mitochondrial MCT (mMCT), or MCT1, MCT4 in the plasma membrane). In the mitochondria, lactate may be converted into pyruvate by the lactate dehydrogenase (LDH). Lactate released into the extracellular space lowers the pH (acidification of the TME) and has an impact on tumorigenesis: lactate (i) supports angiogenesis; (ii) increases cell motility, migration and dissemination; (iii) promotes immune escape, decreases T cell activation and cytotoxic activity (iv) enters by neighboring tumor cells and non-tumor cells (via MCT1, MCT4) .
- Obese patients are at increased cancer risk, which is explained by the presence of dysfunctional adipocytes and pre-adipocytes. These cells release fatty acids (FFAs), adipokines and pro-inflammatory factors. The inflammatory environment and the FFAs promote cancer.
- HIF1a, c-Myc and Tp53 contribute to the metabolic switch in tumor cells: they increase glucose uptake by GLUT1. Moreover, lactate dehydrogenase (LDHA) activity is promoted by HIF1a, c-Myc and Tp53. Tp53 and HIF1a interfere with entry of lactate into the mitochondria and favor the uptake of lactate by neighboring cells.
- The expression of PKM isoforms (PKM1, PKM2) contributes to the metabolic switch: both pyruvate kinases (PK) are encoded by the same gene (PKM gene). When differential splicing includes exon 9 the PKM1 is produced; inclusion of exon 10 generates PKM2. PKM1 functions as tetramer and is always highly active. PKM2 forms an active tetramer or a quite inactive dimer. ROS (reactive oxygen species), tyrosine kinases and several oncogenes (e.g. cMyc) lead to formation of the PKM2 dimer. In the presence of the PKM2 dimer, glycolysis is slowed down and intermediates accumulate. Glucose-6 phosphate and the intermediates enter the pentose phosphate pathway (PPP).
- The PPP produces NADPH and building blocks for biosyntheses, which is very advantageous for tumor cells.
25
Q
Metabolic compartments
- anabolic cancer cells
- catabolic tumor cells
- therapeutic aspects
A
- Cancer cells communicate and cooperatively regulate their metabolism. In the TME anabolic tumor cells reside next to catabolic ones.
- Anabolic cancer cells metabolize glucose by the glycolytic pathway, transport pyruvate into the mitochondria and further metabolize it in
the citric acid cycle (TCA). The reduction equivalents generated in TCA are used in OXPHOS to drive ATP synthesis. Moreover, anabolic cancer cell take up lactate and free fatty acids (FFAs) from the extracellular space and use these metabolites to drive the TCA and OXPHOS. - Catabolic tumor cells carry out aerobic glycolysis and release catabolites, such as lactate. TCA and OXPHOS are largely inactive.
- Whether a cancer cells is an anabolic or a catabolic cells depends on the neighborhood and the distance to the vasculature: anabolic cancer cells are close to the vasculature and have access to nutrients and oxygen. Moreover, catabolites, such as lactate or ketones, are taken up by anabolic cancer cells. Ultimately, these metabolites enter TCA and OXPHOS. Mitochondrial activity is high; ATP production is efficient .
- Therapeutic aspects: Since the metabolic adaptation of tumor cells supports tumor progression, invasiveness and metastasis, it appears conceivable to interfere with the various aspects of the metabolic switch and/or exchange of metabolites/catabolites. One option is inhibition of transporters (GLUT, MCTs). In addition, agents such as metformin and arsenic disrupt crucial pathways and are expected to result in disturbance in cancer cells energy balance.
26
Q
Metabolic switch and stemness
A
- Cancer stem cells, like normal stem cells, prevent accumulation of cytotoxic and harmful metabolites, such as reactive oxygen species (ROS). A major source for ROS are the OXPHOS complexes I, III and IV. Hence, reduction of OXPHOS will drastically reduce the amount of harmful and mutagenic ROS. This is not needed in proliferating progenitors and differentiating cancer cells. CSCs, however, prevent accumulation or production ROS by several ways:
- First, quiescent stem cells and CSCs maintain their mitochondria at an immature level (small mass, few cristae, few enzymes and few functional OXPHOS complexes).
- Second, CSCs block further degradation of pyruvate in the TCA by inhibiting the entry reaction catalyzed by the pyruvate dehydrogenase complex (PDC). This is mediated by the PDC-specific kinase PDK, which is e.g. activated by HIF1a.
- Third, CSCs produce antioxidants, such as glutathione (reduced form = GSH) which counteract ROS. The presence of GSH depends on the presence of NADPH, which may be produced by the pentose-P pathway (PPP), IDHs (NADP-dependent isocitrate dehydrogenases) and ME1 (malic enzyme 1). Mutant IDHs, however, consume NADPH in the production of the onco-metabolite 2-hydroxyglutarate (2-HG).
27
Q
Hematological neoplasms
A
are cancers of the blood, bone marrow, lymph nodes
28
Q
Leukemia
A
is a cancer of the cells in blood or/and bone marrow; the term covers a broad spectrum of diseases; typical: abnormal increase of blood cells, usually leukocytes
29
Q
Lymphoma
A
is a cancer of the lymphocytes; may develop in the lymph nodes, spleen, bone marrow, other organs or blood; -> eventually they form a tumor; two subgroups were defined:
- Hodgkin’s lymphoma (more radiation sensitive)
- non-Hodgkin’s lymphoma (less radiation sensitive)
30
Q
Myeloma (=MM, myeloma, plasma cell myeloma, Kahler’s disease)
A
cancer of the plasma cells which are derived from bone marrow and are transported through the lymphatic system; the plasma cells (plasma B cells, effector B Cells) produce antibodies.
31
Q
Acute lymphoblastic leukemia (ALL)
A
- childhood cancer (age: 1 and 7 years)
- cancer of immature lymphocyte cells (=lymphoblasts)
- an ALL subtype shows the Philadelphia chromosome (Ph)
32
Q
Acute myeloid leukemia (AML)
A
cancer of the immature myeloid cells
33
Q
Chronic lymphocytic leukemia (CLL)
A
- cancer of the lymphocyte cells.
- most common type of leukemia in adults (rare in children)
34
Q
Chronic myeloid leukemia (CML)
A
- cancer of the neutrophils cells.
- a CML subtype shows the Philadelphia chromosome (Ph)
- rare in children, affects adults.
35
Q
Symptoms leukemia patients
A
feeling sick, fever, chills, night sweat; flu-like symptoms; feeling fatigued; nausea feeling of fullness (enlarged liver, spleen); When leukemic cells invade the central nervous system neurological symptoms (e.g. headaches) occur; due to malfunctioning of immune system cutaneous manifestations are observed.
-> QUITE UNSPECIFIC
36
Q
Symptoms Non-Hodgkins’ Lymphoma patients
A
Swollen lymph nodes; unexplained weight loss; fever; night sweats; coughing, trouble breathing or chest pain; weakness and tiredness; pain; swelling or a feeling of fullness in the abdomen.
-> QUITE UNSPECIFIC
Both, Hodgkin and non-Hodgkin lymphoma may be related to infection with EBV (Epstein Barr Virus)
37
Q
Classification and Nomenclature (acute vs chronic; lymphoblastic vs myeloid)
A
Classification criteria are (i) acute versus chronic, (ii) lymphoblastic cancer versus myeloid cancer.
Acute versus chronic:
(a) acute: rapid occurrence and progression; rapid accumulation of immature blood cells; malignant cells spill over into the bloodstream and spread to the organs; most common form of leukemia in children.
(b) chronic: progress takes months or years; increase of relatively mature, but abnormal, white blood cells; cancer cells are produced at a much higher rate than normal cells; treatment immediately but sometimes only monitoring for long time periods before treatment starts; at any age, but mostly in older people.
lymphoblastic versus myeloid cancer:
(a) Lymphoblastic (lymphocytic): cancerous change in the marrow cell that normally differentiates into lymphocytes, affects B cells, T cells and NK cells.
(b) change in the marrow cells that normally differentiate into white blood cells; Myeloid (myelogenous): cancerous affects dendritic cells, granulocytes and macrophages, red blood cells, platelets.
38
Q
Neoplasm - Mantle cell lymphoma (MCL)
A
- Mantle Cell lymphoma (MLC): aggressive, rare, form of non-Hodgkin lymphoma (NHL) that arises from cells originating in the “mantle zone” of secondary lymphoid organs, where B cells mature (hyper-mutation, DNA rearrangements).
- Two major driver mutations have been identified: (i) inactivation of the kinase ATM; (ii) t(11,14) translocation: the CCND1 gene is inserted into the heavy chain (IGH) locus on chromosome 14, leading to over-production of Cyclin D1 (in 90 % of MCL cases).
39
Q
Neoplasm - Burkitt’s lymphoma (BL)
A
Three variants exust: (i) the classical African or endemic type of Burkitt’s lymphoma; (ii) the sporadic type (non-African type), and (iii) the immunodeficiency-associated variant (HIV-infected patients; immunosuppressed transplanted patients).
- chromosomal changes are often observed in patients with Burkitt’s lymphoma; highly frequent: t(8;14)(q24;q32).
- 8q24: c-myc proto-oncogene.- 14q32: immunoglobulin heavy chain gene locus (IgH).
- the t(8;14) translocation brings the c-myc gene under the control of the IgH promotor, leading to c-Myc over-expression.
40
Q
Neoplasm - chronic myeloproliferative disorders
A
- Mutations of receptor tyrosine kinases (e.g. cKit, PDGF receptors) and Janus kinases, JAKs, (most often JAK2).
- JAKs show a common domain structure: receptor interacting domain (JH3-5, JH6-7), pseudo kinase domain (JH2), kinase domain (JH1). JH2 regulates the activity of the kinase domain JH1 and thereby exerts an “auto-inhibitory effect”.
- Two JAKs bind to a cytokine receptor dimer; the kinase of the one JAK phosphorylates the second JAK; moreover, the JAKs phosphorylate the STAT signaling molecules.
- Replacement of valine 617 by phenylalanine in the JH2 domain (=JAK2 V617F) abrogates the inhibitory effect of JAK pseudokinase domain onto the kinase activity. This leads to a partially active conformation.
- The JAK2 V617F may trigger neoplastic transformation of myeloid cells ( -> chronic myoproliferative disorders).
41
Q
C-Myc dysregulation
A
- Proper function of c-Myc is needed at all levels of differentiation of B-lymphocytes
- The translocations t(8;14); t(2;8); t(8;22) bring the c-myc proto-oncogene under the control of an immunoglobulin
promoter: this induces overexpression of c-myc and contributes to Burkitt’s lymphoma, multiple myeloma and other cancers. Additional activation mechanisms leading to neoplasms of the hematopoietic system include (i) increased mRNA stability, (ii) epigenetic deregulation of the promoter, (iii) c-Myc self-induction and (iv) increased c-Myc protein stability.
42
Q
cABL dysregulation
A
- cABL is a tyrosine kinase which is encoded by the proto-oncogene c-abl (human chromosome 9).
- cABL is present in the cytoplasm and the nucleus; it regulates proliferation & survival, and affects the cytoskeleton.
- The t(9;22) (= Philadelphia chromosome; Ph) translocation may generate three distinct BCR-ABL fusion proteins due to variations in the BCR moiety. The Ph is sufficient to induce leukemia and, in the respective contexts, necessary to maintain leukemia.
- The wildtype BCR (= breakpoint cluster region) protein: is a Ser/Thr kinase; is a GEF for Rho GTPases
- All BCR-ABL fusion proteins display oncogenic functions; i.e. they interfere with DNA repair and they possess a constitutively active ABL tyrosine kinase. Moreover, BCR provides the ABL tyrosine kinase with a oligomerization domain and BCR directs the fusion protein to the cytoplasm.
- Many signaling pathways are affected by BCR-ABL: cell adhesion and migration is altered; DNA repair is disrupted, proliferation and survival is increase, BCR-ABL is “anti-apoptotic”.
- cABL and BCR-ABL are inhibited by Imatinib. In leukemia, Imatinib may interfere with function of deregulated cKit, PDGF receptors alpha and beta.
43
Q
Acute promyelocytic leukemia (APL)
A
- > Molecular analyses identified specific translocations in APL (acute promyelocytic leukemia)
- > APL patients show increased numbers of promyelocytes due to a differentiation block.
- > Dysregulation of RARa (retinoic acid receptor alpha) signaling after translocation is critical.
- > The t(15;17) translocation fuses a truncated RARa to a truncated PML (Promyelocytic leukemia protein)
