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Molecular Basis of Disease > Pancreatic cancer > Flashcards

Pancreatic cancer Flashcards

1
Q

What is the pancreas?

A

Pale-grey gland located in the upper abdomen behind the stomach

Between the duodenum and spleen

Around the left side

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2
Q

What does the pancreatic duct do?

A

It joins the pancreas to the common bile duct, supplying pancreatic juice (exocrine) which aids in digestion

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3
Q

What is pancreatic juice?

A

A mixture of water, salts, bicarbonate, and many different digestive enzymes (amylases, lipases, proteases)

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4
Q

What is one of the factors (related to anatomy) which makes surgery on the head of the pancreas difficult?

A

The mesenteric artery is pressing right around the head of the pancreas

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5
Q

What does the exocrine pancreas do?

A

It secretes enzymes that digest carbs, proteins, fats, and bicarbonate for neurtalising acid chyme

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6
Q

What is the functional unit of the exocrine pancreas?

A

Acini

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7
Q

Where do the acini get their name?

A

The are formed by acinar cells

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8
Q

What are the cellular units of the endocrine pancreas?

A

Islets of langerhans

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9
Q

What is the main difference between the exocrine and endocrine pancreas?

A

Endocrine: released directly into blood
Exocrine: released into pancreatic duct

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10
Q

What would you see in a slide of the pancreas?

A

Acini and ducts
Islets of langerhans
Blood vessels
Stroma

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11
Q

What cells do the islets of Langerhans contain (and what do they secrete)?

A 
A cells - glucagon
B cells - insulin 
D cells - somatostatin
G cells - pancreatic polypeptide
E cells - ghrelin
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12
Q

What is one of the things somatostatin does?

A

glucagon and insulin regulation

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13
Q

what does ghrelin do?

A

causes the sensation of hunger

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14
Q

Why is pancreatic cancer something we should care about (other than all diseases generally sucking)?

A

It is one of the top 10 most lethal forms of cancer (<7% survival)

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15
Q

What percentage of pancreatic cancers develop in the head?

A

75%

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16
Q

what is the incidence of pancreatic cancer per year?

A

10 per 100,000

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17
Q

What sort of metastases are typical of pancreatic head tumours?

A

Going through the bile duct to the liver

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18
Q

What are the limitations in pancreatic cancer?

A

Highly fibrotic stroma acting as a mechanical barrier to drugs

Inter and intra tumoural heterogeneity

genetic complexity (many different mutations)

MDR

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19
Q

TRUE or FALSE? Pancreatic cancer like many other cancers has had huge improvements in survival.

A

FALSE

While other cancer prognoses have improved, pancreatic cancer survival has remained very bad over the years

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20
Q

TRUE or FALSE? It is expected that pancreatic cancer will continue to kill the same number of people as it is now in the future

A

FALSE

We think it’ll kill more people

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21
Q

What proportion of patients are diagnosed as an emergency and how does this affect their prognosis?

A

Half

Late diagnosis –> worse prognosis

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22
Q

What is the gender distribution of pancreatic cancer?

A

About equal between men and women but is now affecting men more than women

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23
Q

Does pancreatic cancer research get much money?

A

No, because the survival is so low and people die so quickly

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24
Q

When people are diagnosed with pancreatic cancer how much does this increase their survival?

A

x10 their five year survival

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25
Q

What percent of people diagnosed with pancreatic cancer survive beyond 5 years?

A

4%

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26
Q

What is one simple factor which is contributing to the increase in pancreatic cancer?

A

The aging population

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27
Q

What are the inherited risk factors for pancreatic cancer?

A

Family history: The risk is increased 6-fold in those with 2 affected relatives

The BRCA2 gene conveys a 3.5 fold risk of pancreatic cancer

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28
Q

What percentage of pancreatic cancer is inherited?

A

10%

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29
Q

What are acquired pancreatic cancer risk factors?

A 
Top :
Obesity
Smoking
Diabetes
Pancreatitis
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30
Q

Check name as many pancreatic cancer risk factors as you can

A 
Family history
diet: too much meat and not enough veg
obesity
race
smoking 
gender
age
diabetes
pancreatitis
Alcohol: >5yrs of heavy drinking, not binges,only x1.2%
31
Q

How much does smoking cessation reduce risk in 2 years?

A

48%

32
Q

How much of pancreatic cancer is caused by smoking?

A

20-30%

33
Q

Which ethnic groups are more likely to get pancreatic cancer?

A

African-americans
ashkenazi jews
Maori
incidence increasing in Asia

34
Q

Define pancreatitis and its acute and chronic form

A

Pancreatitis: Inflammation of the pancreas

Acute: Episodic, pancreas heals, no sequelae

Chronic: Protracted, pancreatic damage, permanent
- a condition where the pancreas becomes permanently damaged due to inflammation

35
Q

very simply, what causes pancreatitis?

A

Inflammation can, for example, block off the opening into the common bile duct –> autodigestion –> inflammation –> autodigestion –> and so on

36
Q

Explain the pathogenesis of pancreatitis

A

Damage to acinar exocrine cells –> activation of pancreatic enzymes (e.g. trypsin) –> local inflammation, oedema, autodigestion, release of cytokines, activation of leucocytes

37
Q

What can damage acinar exocrine cells?

A

direct toxic effect (alcohol)
obstruction and back pressure
reflux of bile
increased Ca2+

38
Q

What are the symptoms of pancreatic cancer?

A

Clinically silent until advanced stage

Loss of appetite
Jaundice
Pain in abdomen and back
Change in bowel habits
Nausea
Weight loss
New onset diabetes
39
Q

What is the peak age of onset for pancreatic cancer?

A

65-75 yrs

40
Q

Where in europe is pancreatic cancer more common?

A

Portugal, Denmark, Ireland

41
Q

What are the main types of pancreatic neoplasms?

A

Exocrine:
Ductal adenocarcinoma - 90%
Cystic neoplasms - <1%

Endocrine:
Neuroendocrine tumours (islet tumours) - <5%
42
Q

What are the most lethal and least lethal pancreatic neoplasms?

A

Most: ductal adenocarcinoma

Least: Neuroendocrine tumours (slow growth) - people live longer because it is less agressive althoug there is no cure
- steve jobs had this

43
Q

What are the requirements for a pancreatic tumour to be considered benign and give an example?

A

<3cm in size

e.g. serous cystadenoma

44
Q

Give 2 examples of malignant pancreatic tumours

A

Mucinous cystadenoma: cyst filled with a thick fluid called mucin (tail, women)

Intraductal papillary mucinous neoplasm: cystic tumour that grows from the main pancreatic duct of from side branches of the duct

45
Q

Give us a brief idea of what the differential diagnoses for a pancreatic cyst can be

A

Benign: Pseudocyst, serous cyst adenoma

Malignant potential: mucinous cyst adenoma, intraductal papillary mucinous neoplasm (branch duct IPMN)

Malignant: pancreatic duct adenocarcinoma, solid pseudopapillary neoplasms, PNET

46
Q

Why is pancreatic cancer a complex disease?

A

Progressive accumulation of genetic alterations in different oncogenes and tumour suppressing genes are associated with PanCa progression.

47
Q

What are the 4 major driver genes for pancreatic cancer?

A

KRAS
CDKN2A/p16
TP53
DPC2/SMAD4

but there are many other genetic and epigenetic changes all leading to aberrant signalling pathways

48
Q

What are PanINs?

A

Pancreatic intraepitheial neoplasias: Histological changes associated with the early development of PanCa

Most common precursor lesions of PDAC.

49
Q

How does PDAC progress?

A

Gene mutations, transcriptomic, proteomic, and epigenetic changes occur in parallel with the development of PanIN lesions.
Meanwhile, inflammatory cells infiltration promotes growth and invasion.

Mutations in order:

  1. Telomere shortens
  2. Mutations of K-RAS
  3. Inactivation of p16
  4. Inactivation of p53, SMAD4, BRCA2
50
Q

What are the roles of different mutated genes in PDAC progression?

A

KRAS mutations - predominantly driving activating mutations

CDKN2A inactivation and P53 loss - deregulation of cell cycle

SMAD4 mutations - disregulation of TGF-β signalling.

51
Q

What process allows pancreatic tumours to metastasize?

A

Epithelial-mesenchymal transition

52
Q

What are the steps of EMT?

A
  1. cells get different characteristics that allow them to move
  2. Intravasation: invasion of cancer cells through the basal membrane into a blood or lymphatic vessel
  3. Systemic dissemination
  4. Extravasation
  5. Dormancy
  6. Colonization
  7. Formation of a secondary tumour
53
Q

What are the main drivers of EMT in pancreatic cancer?

A

Transcription factors: Snail, Slug and Zeb1

which are in turn regulated by cytokines (TNF-α), growth factors (TGF-β), and microRNAs.

54
Q

What do these transcription factors do to cells leading to EMT?

A

Epithelial: non- invasive, chemo-sensitive cells, making E-cadherin and cytokeratin

into

Mesenchymal: invasive, chemo-resistant cells that have stem-cell-like properties, making vimentin and fibronectin

55
Q

What is a hallmark of PDAC?

A

Very fibrotic stroma: dense collection of fibroblasts (pancreatic stellate cells)

+

new blood vessels and ECM proteins (connective tissue: collagen type 1, glycoproteins)

56
Q

What effect does the fibrosis have on the aggressiveness of the cancer?

A

It makes it more aggressive, decreases drug delivert

Cancer-associated fibroblasts are implicated in multiple tumour promoting roles

57
Q

What are the characteristics of activated pancreatic stellate cells?

A 
Increased proliferation
migration
ECM deposition
Myofibroblast -like
MMP secretion
making alpha-SMA, fibroblast activating protein, glial fibrillary acid protien, tenascin C
58
Q

What effects do activated pancreatic stellate cells have on other cells?

A

Beta cells: increase apoptosis, decrease insulin

Neurons: Increase cancer-directed migration and growth

Endothelial cells: increased proliferation and tube formation

Cancer cells: Increase proliferation, migration, decrease apoptosis

T cells: decrease activity

Mast cells: increase activation

Myeloid-derived suppressor cells: increased migration

59
Q

What factors activate pancreatic stellate cells

A
  1. Cytokines (IL-1, IL-6, TNF–α)
  2. Growth factors (PDGF, GF–1)
  3. Ethanol and its metabolites
  4. Oxidative stress
  5. Pressure
  6. Extensive changes in ECM (composition and organization)
60
Q

What is the source of PS activating factors

A

Endothelial cells in inflamed pancreas

pancreatic cancer cells

61
Q

How do you manage pancreatic cancer?

A

20% - Surgery

80% - (locally advanced and metastatic) –Palliative treatment

62
Q

What does pallative treatment involve?

A

chemotherapy + best supportive care

63
Q

Same different treatments for pancreatic cancer

A

Gemcitambine (first line) +capecitabine

Folfirinox - side effects are horrible

Gamcitabine +abraxane (nab-paclitaxel) - very expensive (controversy about whether people can get it)

64
Q

What are neuroendocrine tumours (PNETs)?

A

Neoplasms that arise from endocrine stem cells

65
Q

How do PNETs differ from PDAC?

A

Less common and better prognosis (usually small, < 1cm)

Slow growing and are often best treated surgically

Rare: <5%

66
Q

What are the types of PNETs?

A

Functional (secrete hormones: e.g. insulin, glucagon) or non-functional

67
Q

What markers do PNETs secrete?

A

synaptophysin and chromogranin

68
Q

TRUE or FALSE? PNETs usually metastasize before becoming symptomatic

A

TRUE

69
Q

Which are more dangerous functional or non functional PNETs?

A

Functional

70
Q

What kind of functional PNETs are there and what do they do?

A

Insulinoma - hypoglycemia

Gastrinoma (gastrin) - peptic ulcer, diarrhea, GERD

glucagonoma - necrolytic migratory erythema, diabeters, depression

Somatostatinoma - diarrhea, diabetes, hypochlorhydria, cholelithiasis

VIPoma - watery diarrhea, hypokalemia, achlohydria

71
Q

How do non functional PanNETs present and what do they secrete?

A

Secrete: pancreatic poly peptide, neurotensin, ghrelin

Symptoms: Mass-related= jaundice, pancreatitis

72
Q

Since early detection is so important, how is early pancreatic cancer diagnosis done?

A

Blood/urine samples can be collected and checked for biomarkers

Tumours shed proteins: CA125,CA19-9, PSA

Body responding to tumour: inflammatory response

73
Q

What does the drug abraxane do and what are the problems with it?

A

It attacks the stroma but because there are 4 types of fibroblasts you might kill the good ones and lead to increased cancer growth

74
Q

What are the biological targets for cancer therapy?

A
  1. GFs and their receptors
  2. Signal transduction pathways
  3. Tumour associated antigens/markers
  4. Proteosome
  5. Cell survival pathways
  6. ECM/angiogenic factors

Molecular Basis of Disease (28 decks)

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