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Year 2 Med > Neoplasia > Flashcards

Neoplasia Flashcards

1
Q

What is neoplasia?

A

Autonomous/independent growth of an abnormal cell or tissue, the growth of which is more rapid than normal tissues and continues to grow after the stimulus that initiated the new growth is removed

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2
Q

What are the types of tumour?

A
  • carcinoma in-situ
  • invasive
  • metastatic
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3
Q

What is dysplasia?

A
  • Disorderly growth of epithelium -confined to epithelium.
  • Reversible.
  • When the entire epithelium is dysplastic and no normal epithelial cells are left, then the process is beyond dysplasia and is now neoplasia.
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4
Q

What is carcinoma in-situ?

A

basement membrane is still intact and carcinoma is still confined to the epithelium

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5
Q

What is invasive carcinoma?

A

neoplastic cells invade the BM

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6
Q

Benign vs malignant tumour

A

Benign neoplasm: it is well circumscribed, slow growing, and resembles the tissue of origin (fat).

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7
Q

What is angiogenesis in health vs disease?

A

Health
 Development and growth
 Reproductive system
 Repair
Disease
 Vascular malformation
 Chronic inflammatory disease
 Malignant tumours

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8
Q

What is the process of metastasis?

A

1)Growth and angiogenesis of primary tumour- EMT transition (mesenchymal cells are more motile)
2)Local invasion
3)Penetration of blood vessels or lymphatics (intravasation- into bloodstream)
4)Survival in the circulation (CTCs)
5)Arrest and escape from blood vessels or lymphatics (extravasation- exit from bloodstream)
• Colonisation and angiogenesis at the new secondary site

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9
Q

What are the routes of tumour spread?

A
  • Blood vessels
  • Lymphatic system
  • Movement within body cavities (peritoneal and pleural)
  • Neural
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10
Q

What are the patterns of tumour spread?

A

Direct Extension-

  • Binding to extracellular membrane (ECM)
  • Enzymatic lysis of ECM

Metastasis-

  • Invasion/penetration of blood/lymph vessel
  • Release of tumour cells into circulation (CTCs)
  • Arrest of emboli – small vascular channels in distant organs
  • Growth of tumour in arresting vessels – spread to adjacent tissue
  • Neovascularisation
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11
Q

What are the bio markers of cancer?

A
  1. Fetal proteins- AFP Teratomas, hepatomas; CEA – GI tumours
  2. Hormones- HCG – teratomas, chorio carcinoma
  3. Tumour associated antigens- CA125 – ovary; PSA - prostate
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12
Q

What are the uses of biomarkers?

A
  1. Screening for cancer in a general population
  2. Diagnosis
  3. Classification: staging, localisation, classification Estimation of tumor volume
  4. Efficacy of treatment/ prognosis.
  5. Detection of disease recurrence/relapse
  6. Prognostic indicators of disease progression.

Roles of cancer biomarkers can be defined as prognostic, diagnostic or predictive

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13
Q

What cell type is most cancers?

A

Epithelial- carcinoma

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14
Q

What are the classes of genes implicated in the onset of cancer?

A
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15
Q

How are oncogenes activated and tumour suppressor genes inactivated?

A
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16
Q

What is the non-cellular component of the local environment of a cancer?

A

• Mesh-like structure composed of different proteins and molecules secreted by the resident cells.
• Collagen provides ECM its structure – also contains fibronectin and laminin. Act as anchors for cells – bind with integrins.
• Proteoglycans (proteins with polysaccharide chains) fill up the remaining space. Are able to bind to soluble growth factors and keep them sequestered.
• ECM is a dynamic structure – components are subject to various modifications through the activity of the surrounding cells such as
macrophages and fibroblasts. Allows the ECM to be remodelled to favour cellular processes in order to maintain tissue homeostasis.

17
Q

What is the role of the ECM in cell migration?

A

Ø When required, cells are able to move along the ECM.
Ø For a cell to move, it forms a leading edge which firmly attaches to the ECM.
Ø This attachment is between integrins of the cell and fibronectin of the ECM which allows the cells to move forward.
Ø Collagen fibres can be cross linked which can be arranged as tracks to facilitate cell migration.
• To migrate, cancer cells transform themselves to become more mesenchymal through the epithelial-mesenchymal transition (EMT)
process

18
Q

How does cancer progress?

A

• Cancer progression starts in a dividing cell.

• The activity of oncoproteins provides the proliferative signal for cells to continue dividing even without any stimulus.

• Combined with this, the loss of tumour suppressors enable cells to escape any growth inhibitory restraints.

• Cancer development is often viewed as a culmination of mutations within the malignant cells and, as such, much of modern targeted cancer therapy has been based on our understanding of these mutations and how they change cellular behaviour.

• However, it is now understood that cancer cells do not act alone but establish complex interactions with their surrounding microenvironment.

• These interactions contribute to almost all of the hallmarks of cancer and offer opportunities for more targeted cancer therapy

• Epithelium tissue is supported by the basal lamina and a layer of connective tissue called the stroma. Immune cells, fibroblasts, pericytes reside within the stroma.
• Cancer cells are able to corrupt the behaviour of these cells to supply themselves with the necessary proteins and other molecules to aid cancer progression.

• Corrupted macrophages are called tumour associated macrophages (TAMs) and fibroblasts as cancer associated fibroblasts (CAFs).

• As cancer cells progressively become abnormal and acquire
different hallmarks they gain the capability to influence the local environment turning it into a tumour microenvironment (TME).

• Within the TME, cancer cells recruit immune cells and fibroblasts as sources of growth factors for their proliferation and proteases for remodelling the ECM.

• Cancer cells also communicate with endothelial cells with the aim of activating them. Activated endothelial cells start to generate new blood vessels to support the growth of the tumour.

19
Q

What is the tumour microenvironment and how does this impact the survival of cancer cells?

A
  • The conditions within the tumour microenvironment differ considerably from those in a normal cellular microenvironment.
  • Major changes include:
    Ø Hypoxia (low oxygen levels)
    Ø Low pH (acidic conditions)
    Ø Low glucose levels
  • In order for cancer cells to sustain themselves and continue to proliferate they need access to the blood system to obtain adequate supply of oxygen and nutrients.
  • Hypoxia triggers cancer cells to produce VEGF. This acts as a ligand for VEGFR present on endothelial cells. VEGR signalling is relayed through MAPK pathway to trigger cell proliferation.
  • Cancer cells within the TME respond to low oxygen levels by activating hypoxia- inducible factors (HIFs).
  • HIFs are transcription factors which enable the cells to turn on the necessary genes to adapt to the hypoxic environment.
  • These genes code for key proteins and enzymes that maintain the TME e.g. VEGF.
  • The hypoxic condition further exacerbates the corruption of the TME and can promote changes that favour tumour progression.
  • The hypoxic condition results in generation of free oxygen radicals which can cause mutations.
  • This increases genetic instability in both cancerous and non-cancerous cells.
20
Q

What is the role of TAMs (tumour associated macrophages) in cancer progression?

A
  • The TME is found to be infiltrated with immune cells, especially macrophages.
  • Cancer cells use chemoattractants such as CSF-1 and IL-1b to attract macrophages and transforms them into tumour-associated macrophages.
  • TAMs act to support cancer progression. They release growth factors such as EGF which helps cancer cells proliferate and
    VEGF which acts on endothelial cells to sustain angiogenesis.
  • Crucially they also secrete proteases which act on the ECM.
  • The proteases liberate the sequestered growth factors which re-enforce the proliferative signals for cancer cells, endothelial cells and fibroblasts
21
Q

How do cancer-associated fibroblasts (CAFs) transform the ECM?

A
  • CAFs are the major cell type found within the TME.
  • They are mostly derived from normal fibroblasts and are referred to as being ‘activated’.
  • Cancer cells use signalling proteins such as Hedgehog and PDGF to activate fibroblasts.
  • The activated status now ensures that they produce high levels of collagen and other enzymes to remodel the ECM.
  • Furthermore, collaborating together, they use lysyl oxidase, which crosslinks collagen to form tracks for cancer cells to migrate on.
  • CAFs also produce a wide range of signalling molecules including VEGF and FGF which contribute to angiogenesis.
22
Q

How does p53 regulate angiogenesis?

A
23
Q

What factors contribute to tumour heterogeneity?

A
24
Q

What is clonal evolution

A

stepwise acquisition of mutations

25
Q

Intra tumour vs inter tumour heterogeneity?

A
  • Within a tumour, subclonal diversity may be observed (intratumour heterogeneity).
  • Subclones may intermingle (as shown by subclones 1 and 2) or be spatially separated (as shown by subclone 3).
  • Separation between subclones could reflect physical barriers such as blood vessels or micro-environmental changes.
  • Intercellular genetic heterogeneity is exacerbated by genomic instability and may foster the emergence of tumour subclones.
  • Genomic instability and tumour subclonal architecture may vary further over time if influenced by, for example, cancer treatment.
26
Q

What are the hallmarks of cancer?

A
27
Q

What are the main pathways implicated in genomic instability

A

● Base and nucleotide excision repair:
Ø Function to excise and repair abnormal bases or nucleotides, such as deaminated cytosines.
Ø Germline mutations of these pathways predispose people to colonic polyposis or skin cancers.

● Mismatch repair:
Ø Acts during DNA replication to correct base mismatches, as well as insertions and deletions at repetitive sequences (microsatellites).
Ø Loss of function of MSH2 and MLH1 results in hypermutation and microsatellite instability.

● Double-strand break repair:
Ø Homologous recombination repair of double-strand breaks (DSBs) uses the sister DNA molecule as a template to repair the break (BRCA1 & BRCA2).
• Important for repair of stalled or collapsed replication forks.
Ø Non-homologous end joining directly ligates the DSB in an error-prone manner (BRCA1).
• Defects in DSB detection or repair result in chromosomal instability, with an elevated rate of structural chromosomal rearrangements and point mutations.

● DNA replication:
Ø Deregulated DNA replication can result in replication fork stalling, reversal and collapse.
Ø Deregulation can occur through oncogene activation, loss of certain tumour suppressors, DNA polymerase
inhibition, nucleoside imbalances, replication-blocking DNA lesions and clashes of replication forks with
ongoing transcription.
Ø Replication stress can trigger DNA DSB formation (particularly at genomic fragile sites), unscheduled
recombination events and chromosomal rearrangements.

● Chromosome segregation:
Ø Defects in chromosome segregation can arise directly through defects in the mitotic checkpoint, sister
chromatid cohesion, spindle geometry and spindle dynamics.
Ø Result in aberrant chromosome-spindle attachments, and mis-segregation of chromatids during anaphase,
generating aneuploid daughter cells.
Ø Indirect segregation defects can be caused by structural chromosome rearrangements generated before
mitosis, via replication stress, defective repair or telomere fusion.

● Telomere maintenance:
Ø Telomere erosion or uncapping results in catastrophic chromosomal instability.
Ø Reactivation of telomerase expression in cancer cells can alleviate this instability

28
Q

Cancer can result from the expression of mutant forms of seven types of proteins:

A

(I) Extra-and intra-cellular signaling molecules
(II) Signal receptors
(III) Signal-transducing proteins
(IV) Transcription factors
(V) Cell-cycle control proteins, which function to restrain cell proliferation
(VI) DNA-repair proteins
(VII) Apoptotic proteins – tumour suppressors that promote apoptosis and oncoproteins that promote cell survival

Year 2 Med (60 decks)

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