Tumor Biology Brummer/Hecht/Baumeister

Oncogenes: Tumourigenesis due to dysregulated gene expression and/or gene product activity (gain-of-function mutation) e.g. RAS, Src (v-Src Rous sarcoma virus), onc

Tumorsuppressor genes: Tumourigenesis by loss of gene expression and/or function (loss-of-function mutation) e.g. Retinoblastoma (cell cicle break by binding E2F) , p53 (guardian of the genome),

oncogenes: Raf-Ras, Src (v-Src), onc (v-onc), Myc (far downstream in signaling directly on Transcription), Bcr-Abl (chromosome shortened and bcr and abl fuse forming signaling complex [Gleevec as allistoric inhibitor] [Leukemia])

tumour suppressor genes: p53 —> p21 —> Cycline, BRCA1 (organises the DNA repair multi-protein complex)[Angelina Jolie heredetary], Retinoblastoma (cell cycle break when it binds E2F)

gain of function (oncogenes hyperactive) —> point mutations, insertions, translocations

loss of function (inactivation of tumor supressor genes) —> premature stop codons, epigenetic silencing, loss of genes/chromosomes

To cause cancer a defect tumor suppressor system is needed often a mutation in p53 (the guardian of the genome) e.g. Leberflecken stop growth at some point because of tumor supressors

If only Ras is mutated it does cause permanent activation of many genes because it is upstream of many signaling pathways —> hypeactivity especially cell growth and division (in immortalized cells that mutation can cause cancer)

Cancer as the disease cannot be inherited, but predispositions that increase the risk for cancer can be inherited e.g. chromosomal defects (BRCA1 or retinoblastoma)

The disease is caused by inherited predispositions and envoiramental impacts.

Extra:

amilial adenomatous polyposis coli, abbreviated FAP, is an autosomal-dominant disorder characterized by the presence of multiple adenomatous polyps throughout the gastrointestinal tract —> Colorectal Carcinoma: Carcinoma typically develops about 10 years after polyp onset. The likelihood of colorectal carcinoma is around 10% within the first 5 years, rises to about 30% after 15 to 20 years, and reaches 100% after over 30 years

Tumor supressor genes represent loss-of-function alleles and act in a recessive manner Thus, tumours have usually lost both copies of TSG

• p53 represents an exception, most tumours rather express dominantnegative mutants that impair the function of wildtype p53

• While oncogenes are usually acquired somatically, TSG mutations can be passed on via the germ-line, resulting in earlier tumour onset (Knudson two hit hypothesis, loss-of-heterozygosity)

Because its a defect in a gene coding for retina proteins that only appear in the eye (only there is a retina) also high energy in building of the eye in developement

1. Lytic Infection:

   • In a lytic infection, the virus enters the host cell, replicates within it, and eventually causes the cell to burst (lyse), releasing new viral particles. Lytic infections are typically associated with the rapid destruction of host cells.

2. Transforming Infection:

   • Transforming viruses, on the other hand, do not necessarily cause immediate cell death. Instead, they can induce a transformed state in the host cell, promoting uncontrolled cell growth and division. This transformation may eventually lead to the development of tumors or cancer

—> a tumor cell is not likely to be lytic, if that was the case the cells would have been destroyed in the lyse and the tumor couldnt form

1. Slowly Transforming Retroviruses:

   • Slowly transforming retroviruses, such as the human T-cell lymphotropic virus type 1 (HTLV-1), have a longer latency period before inducing cell transformation. The process of transformation is gradual, and infected cells may not show immediate signs of uncontrolled growth. HTLV-1 is associated with adult T-cell leukemia/lymphoma (ATL), a type of cancer.

2. Acutely Transforming Retroviruses:

   • Acutely transforming retroviruses, like the Rous sarcoma virus (RSV), can rapidly induce cell transformation and tumor formation. RSV was the first retrovirus discovered to cause cancer in animals. It carries the v-src oncogene, which is a mutated form of the host cell's c-src gene, involved in cell signaling and growth

Differences in Mechanisms:

• Slowly Transforming Retroviruses:

  • Typically encode viral proteins that interfere with the host cell's regulatory pathways over time.

  • Induce genetic alterations in a stepwise manner, leading to the gradual development of a transformed phenotype.

• Acutely Transforming Retroviruses:

  • Carry viral oncogenes that are derived from cellular genes (proto-oncogenes) but have acquired mutations that confer oncogenic properties.

  • Rapidly induce cell transformation and uncontrolled growth.

Bcr-Abl is a tyrosine kinase signaling complex that after reciprokal translation of chromosome 9/22 where the philadelphia chromosome 22q- is formed and bcr fuses with abl —> Bcr-Abl fusion protein has constitutive tyrosine kinase activity, leading to uncontrolled cell growth and division, a hallmark of cancer (associated with form of leukemia)

The therapy in this case is a drug that blocks the active centre of the complex (Imatinib = “Gleevec”) the conceptual difference in this therapy is the specifity of the drug because it has very few side effects —> targeted therapie

Chemotherapie (traditional) targets rapidly dividing cells, which include both cancer cells and some normal cells —> Non-selective and can lead to damage to healthy tissues

Extra: cancer is a special disease because its the own body that causes the disease and not e.g. bacteria or some external damage, thats why fighting cancer normally means fighting the system and other therapies show many side effects because of that

1. Small Molecule Tyrosine Kinase Inhibitors (TKIs):

   • Design and use small molecules that specifically target the tyrosine kinase domain of the overexpressed RTK.

   • These inhibitors interfere with the ATP-binding site of the kinase, preventing phosphorylation of downstream signaling proteins.

   • Example: Imatinib, a TKI targeting the Bcr-Abl fusion protein in chronic myeloid leukemia.

2. Monoclonal Antibodies:

   • Develop monoclonal antibodies that specifically bind to the extracellular domain of the overexpressed RTK, inhibiting ligand binding and receptor activation.

   • This can also trigger antibody-dependent cellular cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC).

   • Example: Trastuzumab targets HER2 in breast cancer.

3. Dual Kinase Inhibitors:

   • Design inhibitors that target multiple kinases, including the overexpressed RTK and possibly related pathways to enhance efficacy.

   • This approach may be especially beneficial if there is crosstalk between different signaling pathways.

   • Example: Lapatinib inhibits both EGFR and HER2.

4. RNA Interference (RNAi) or Small Interfering RNA (siRNA):

   • Utilize RNAi technology to silence the expression of the overexpressed RTK at the mRNA level.

   • This approach can lead to reduced synthesis of the oncoprotein and subsequent inhibition of downstream signaling.

   • Challenges include effective delivery of siRNA to the tumor cells.

5. Protein Degradation Technologies:

   • Explore emerging technologies, such as proteolysis-targeting chimeras (PROTACs), to induce the degradation of the overexpressed RTK.

   • PROTACs can target specific proteins for degradation by the ubiquitin-proteasome system.

   • This approach might offer a novel way to address resistance mechanisms.

6. Immunotherapy:

   • Investigate immunotherapeutic approaches, such as chimeric antigen receptor (CAR) T-cell therapy, that use modified immune cells to target and destroy tumor cells expressing the overexpressed RTK.

   • This approach leverages the patient's immune system for tumor destruction.

7. Combination Therapies:

   • Explore combination therapies by combining RTK inhibitors with other targeted agents, immunotherapies, or standard chemotherapy.

   • Combinations can enhance efficacy, overcome resistance, and address the heterogeneity of tumor cell populations.

Seven steps: 1. Local invasion 2. Intravasation 3. Dissemination 4. Arrest in microvessels 5. Extravasation 6. Micrometastases 7. Colonization (Macrometastases)

Apical / basel polarity

cell-cell-adhesion (tight junctions [gap seals], adherens junctions [actin connect + cadherin], desmosome [intermediate connect], gap junctions [transport channels])

cell-matrix-adhesion (anchorage to the basal-lamina with actin or intermediate with hemidesmosome [collagen, laminin - integrins, collagen/dystonin, plectin, kreatin)

E-cadherin: - adherens junction component —> hold the cells in place next to one-another - transmembrane protein - linked to actin cytoskeleton via catenins (α,β,γ-catenins, p120) - Ca2+-dependent - homophilic interactions

for a tumor to become invasive the cell needs to lose these connections so the cadherins are destroyed e.g. by proteases (Matrix metalloproteases MT1-MMP) or they are inactivated by mutation or downregulation (EMT epithilial-mesenchymal transition)

Integrins: - heterogeneous group of transmembrane proteins, - variable heterodimer formation, 18 types of α- and 8 types of β-subunits - Ca2+ / Mg2+-dependent - intracellular connection to cytokeratins (hemidesmosomes) - extracellular link to basement membrane components -

anchorage dependence

anoikis (cell death / apoptosis if cell is seperated from basal-lamina

a membrane of proteins (laminins and collagens [connected by nidogens + perlecan]) working as a barrier to avoid that cells from one tissue infiltrates other tissues via integrins (connected to laminin) the epithilial cells are anchored to the basel lamina

Laminin / collagen (IV) / perlecan / nidogen / integrin (to cell)

degraded by matrix metallo proteases (MMPs) = proteolysis

gene inactivation by mutation

downregulation of gene activity (epithelial-mesenchymal transition [EMT])

Matrix metalloproteases enable the tumor to break through the basement membrane, disconnect cell-cell connections (cadherin) and cell-matrix connections (integrins) and to create a channel for further invasion (extra cellular matrix degradation, they can activate further proteases

Substrates of MMPs and other extracellular proteases: Integrins, Collagen IV, Laminin, pro-MMP-2, E-Cadherin, Fibronectin, Tenascin, latent growth factors

Normally this programm is present in the developement (blastulation / neurolation) or in wound healing it is induced by a variety of signaling molecules (TGF, FGF …) and the present TF (Snail, Twist, ZEB) induce - loss of epithelial features - gain of motility - gain of invasiveness - protease secretion (MMP-2, MMP-9)

All the induced changes are important for the tumor evasiveness but tumors are not strictly mesenchymal so a MET (mesenchymal-epithelial transition) takes place, other theories are partial EMT or plasticity

• specifity of drugs

• hit the right target in a complex pathway

• find the right treatment (surgery / chemotherapy / radiation / irradiation)