Neoplasia biochem

• Cancer Hallmarks as Therapeutic Targets

  • PARP: poly ADP ribose polymerase
• Proto-oncogenes


  • A group of genes that cause normal cells to become cancerous when they are mutated
  • Encode proteins involved in the control of cell growth
  • Stimulate cell division, inhibit cell differentiation, and stop cell death/ apoptosis
  • Partially or even completely silenced after cellular differentiation is complete
  • Their alteration in structure or expression can activate them to become oncogene
• Oncogenes


  • Arise from alteration (such as mutation or epigenetic modification) of proto-oncogenes that results in complete reactivation or increased expression level or activity
  • Results in abnormal cell proliferation, dedifferentiation, and immortality, turning them to malignant tumor cells
  • Major molecular targets for anti-cancer drug design
• General mechanisms of proto-oncogene activation

  1. Point mutations

  2. Gene amplification of a proto-oncogene

  3. Chromosomal translocation that relocate proto-oncogene

  4. Chromosomal translocations that lead to a fusion between a proto-oncogene and a second gene

  5. Epigenetic alterations
• Mechanisms in viral oncogenicity: DNA viruses

  1. Oncogenic DNA viruses can integrate to host genome and carry their own oncogenes

  2. Viral proteins can operate as constitutive signaling receptors or interfere with the functions of inhibitors of cyclin-dependent kinases
• Mechanism of viral oncogenicity

  1. During G1 phase, Rb protein is hypophosphorylated and bound to E2F transcription factors, forming transcriptional repressor complexes

  2. Upon mitogenic stimulation, cyclin-dependent kinases phosphorylate Rb, releasing E2F proteins to initiate S phase

  3. Viral proteins like E1A, large T antigen, and E7 bind to hypophosphorylated Rb, freeing E2F without mitogenic signals and starting S phase
• Retroviral oncogenes


  • Altered versions of host cellular proto-oncogenes incorporated into the retroviral genome by recombination with host DNA
  • Retroviruses were demoted to mere carriers of oncogenes that are part of the host gene
• Types of Tumor Causing Retroviruses

  • Acutely transforming retroviruses: Change the host cell into neoplastic phenotype
  • Chronic/weakly oncogenic viruses: Replicate using host genome but do not transform the host cell, induce tumor formation through insertional mutagenesis
• Classification of Protooncogenes


  • Ligands: growth factors
  • Growth factor receptors
  • Signal transducers
  • Transcription factors
  • Others, including programmed cell death regulators
• Growth Factors: Clinical importance

  • Low molecular peptides acting as promoters of cell proliferation
  • Regulators of embryonic development and cellular differentiation
  • Promoters of tumor growth and progression in various human cancers through activation of signaling pathways
  • Significant development and clinical use of new drugs against various components of signaling pathways
• Growth Factors: Superfamilies


  • EGF - EPIDERMAL GROWTH FACTOR
  • FGF - FIBROBLAST GROWTH FACTOR
  • TGFβ - TRANSFORMING GROWTH FACTOR BETA
  • VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF)
  • PDGF- PLATELET DERIVED GROWTH FACTOR
  • HEPATOCYTE GROWTH FACTOR
  • INSULIN & IGF'S (INSULIN-LIKE GROWTH FACTORS)
• EGF: Epidermal Growth factor


  • Encodes a member of the epidermal growth factor superfamily
  • A potent mitogenic factor that plays an important role in the growth, proliferation and differentiation of numerous cell types
  • Dysregulation has been associated with the growth and progression of certain cancers
• EGF Ligand Types and Receptor Selectivity

  HB-EGF: Heparin-binding EGF-like growth factor
• Effect of EGFR Signaling

  • EGF-EGFR complex associated with tumor cell invasion and metastasis initiation
  • Ligand overexpression increases EGFR dimerization, activation and kinase mediated signaling, leading to tumor growth
  • Overexpression or constitutive activation of EGFR in many cancers contributes to their proliferation and survival
• FGF: Fibroblast growth factors


  • Contain around 18 known FGF ligands to bind FGFRs
  • Generated in a variety of cells such as macrophages
  • Secreted signaling proteins that signal to receptor tyrosine kinases, and intracellular non-signaling proteins that serve as cofactors
• FGF Ligand Family and Receptor Selectivity


  Four main FGFs
• FGF


  • Act via autocrine and paracrine fashion
  • Exception: FGF19, FGF21, and FGF23 can act as hormone-like
  • Most secreted FGFs bind to Heparan sulfate/ heparan sulfate proteoglycans which act as co-receptors and modulate the dynamics and kinetics of ligand-receptor interaction
• FGF


  • Recognized functions include control cell proliferation, migration, differentiation and survival
  • Physiological roles in earliest stages of embryonic development, during organogenesis, and in adults as homeostatic factors for tissue maintenance, repair, regeneration, and metabolism
  • May act in oncogenic fashion to promote multiple steps of cancer progression
• Transforming Growth Factor (TGF)


  • Have wide range of biological activities
  • TGF-α promote cell proliferation, produced in macrophages and keratinocytes
  • TGF-β serves as tumor suppressor in normal tissues by inhibiting cell proliferation and inducing apoptosis, but promotes tumor progression and invasion if the tumor cells overcome its cytostatic and apoptotic effects
• TGF beta: Dual role

  • Tumor suppressive effects observed in normal cell and early carcinomas
  • Tumor promoting effects seen in later stage cancers
• FGFs and FGFRs


  May act in oncogenic fashion
• FGFs and FGFRs


  • Promote multiple steps of cancer progression by inducing mitogenic and survival signals, as well as promoting EMT, invasion and angiogenesis
• FGF abnormalities in various cancer types
• Transforming Growth Factor (TGF)


  Have wide range of biological activities
• TGF-α


  Promote cell proliferation
• TGF-α


  Member of EGF family
• TGF-α


  Control glial and Schwann cell proliferation and survival of differentiated neurons
• TGF-α


  Also produced in macrophages and keratinocytes
• TGF-β


  Involved in stimulate or inhibit proliferation depending on cell type and growth factor environment
• TGF-β


  Serves as tumor suppressor in normal tissues by inhibiting cell proliferation and inducing apoptosis
• TGF-β


  Promotes tumor progression and invasion if the tumor cells overcome its cytostatic and apoptotic effects
• Tumor suppressive effects of TGF-β

  • Observed in normal cell and early carcinomas, include inhibition of cell proliferation, induction of apoptosis, and inhibition of cell immortalization
• Tumor promoting effects of TGF-β


  • Observed in aggressive and invasive tumors, include induction of epithelial mesenchymal transition (EMT), cell adhesion, migration, invasion, tumor metastasis
• As tumors grow and progress, they generally produce and secrete a large amount of autocrine TGF-β that is then released in the tumor vicinity (act as paracrine)
• Effects of autocrine TGF-β in tumor vicinity

  • Inhibit cell adhesion, induce immunosuppression and angiogenesis, and promote the degradation of the ECM, further contributing to the metastatic process
• Vascular Endothelial Growth Factor (VEGF)


  A member of PDGF/VEGF growth factor family
• VEGF


  • Involved in the promotion of endothelial cell proliferation, vascular permeability and angiogenesis
• VEGF


  Key regulator of tumor angiogenesis in all solid tumors
• Upregulation of VEGF has been shown in various cancers such as prostate cancer
• Upregulation of VEGF is regarded as risk factor for tumor metastasis in colon and breast cancer