Theme 5: Neoplasia - Part 4 Flashcards
What are the three steps in the way malignant tumours behave?
- invasion
- metastasis
- angiogenesis
What does invasion mean?
-invades adjacent normal tissue
How do epithelial cells change in cancer to help the spread?
- in health, epithelial cells are tightly connected, polarised and tethered to each other
- mesenchymal cells are loosely connected, able to migrate
- in cancer, epithelial cells gain mesenchymal properties and can invade and migrate
How do epithelial cells invade and migrate in cancer?
- increased motility
- decreased adhesion
- production of proteolytic enzymes
- mechanical pressure
What are cadherins?
cell to cell adhesion molecule - attaches epithelial cells to EACH OTHER
-a mutation in this will reduce cell-cell adhesion
What are integrins?
cell to matrix adhesion molecule and receptor
changes in integrin expression leads to decreased cell-matrix adhesion
What is the most important proteolytic enzyme in neoplastic invasion?
matrix metalloproteinases
Which cells are matrix metalloproteinases secreted by?
malignant neoplastic cells
What are the three major types of matrix metalloproteinases?
- Interstitial collagenases —> degrade type I, II, III collagen
- Gelatinases —> degrades type IV collagen and gelatin
- Stromelysins —> degrades type IV collagen and proteoglycans
In normal tissue regulation, how are proteolytic enzymes balanced and how does this change in cancer?
tissue inhibitors of metalloproteinases balance matrix metalloproteinases
In cancer, cancer favours ECM breakdown so there are more matrix metalloproteinases
What are the clinical effects of invasion?
- uncontrolled proliferation and invasion –> mass
- mass can occlude/put pressure on vessels
- malignant neoplasms invade along “path of least resistance” -usually blood vessels or nerves. cartilage and bone are extremely resistant to neoplastic invasion
What is metastasis?
tumour spreads from site of origin (primary) to a distant site to establish tumour there (secondary)
-often secondary tumour exceeds primary lesion
What might be presenting clinical features of metastasis?
bone lesions and palpable lymph nodes
What are the 6 steps in the metastatic sequence?
- detachment invasion
- intravasation (invasion of cancer cells through basement membrane into blood vessel)
- survival against host defences
- adherence extravasation - bind to blood vessel and exit
- growth
- angiogenesis
How do neoplastic cells become motile?
loss of surface adhesion molecules and imbalance of proteolytic enzymes that mean the ECM is broken down
What are 3 routes of metastasis?
- Lymphatics
- form secondary tumours in lymph nodes
- most common route initially for carcinomas - Haematogenous (blood)
- commenest route for sarcomas
- organs involved are lungs, liver, bone and brain - transcoelomic
- spread across the peritoneal/ pleural cavity
- will lead to effusion containing neoplastic cells
What is the difference between carcinomas and sarcomas?
carcinomas - cancers that develop in epithelial cells and sarcomas develop in mesenchymal tissue
What is angiogenesis?
growth of blood vessels on existing vasculature
How do tumour cells promote angiogenesis?
they express vascular endothelial growth factor (VEGF)
What does stage mean?
The extent of tumour spread - has the tumour metastasised?
What does grade mean?
how aggressive is the tumour? how different does it look from tissue of origin?
Explain the TNM Tumour staging system?
T - extent of tumour spread:
- T0: no evidence of primary tumour
- T1-T4: increasing size/ invasion of tumour
N- extent of nodal spread
- N0: no regional node metastases
- N1-N3: increasing involvement of nodes
M- presence or absence of distant metastases
-M0: no distant metastases
-M1: distant metastases present
Mx - unable to comment
Explain the Dukes staging system?
For Colorectal cancer:
A- Invades into but not through the bowel wall
B- Invades through the bowel wall, but no LN metastases
C- Local lymph nodes involved
D- distant metastases
How do we stage lymphoma?
Stage I: Lymphoma in one group of lymph nodes
Stage II: lymphoma in 2 or more groups of lymph nodes
Stage III: lymphoma on both sides of diaphragm
Stage IV: lymphoma in other organs/bone marrow/ liver or lung
How is lymphoma further classified?
A - symptoms absent
B- symptoms present e.g fever, weight loss
What factors do we consider when determining the grade of cancer?
- differentiation = how much cancer cells resemble normal tissue
- pleomorphism = the variation in size and shape of cancer cells
- proliferation = mitotic figure, how many cells are actively dividing
What is a poorly differentiated, high grade tumour?
cells hardly resemble those of normal tissue
What are the 6 hallmarks of cancer?
- self sufficiency in growth signals
- insensitivity to anti-growth signals
- tissue invasion & metastasis
- limitless replicative potential
- sustained angiogenesis
- evading apoptosis
Explain the most fundamental trait of cancer cells
ability to sustain chronic proliferation
-intracellular signalling pathways regulate progress and cell growth through the cell cycle
How do cancer cells evade growth suppressors?
- Rb protein prevents progression from G1 to S phase
- inactivating of Rb gene results in resistance to -ve growth regulation
- this causes loss of gatekeeper between G1 and S phase
- so there is continuous growth of the cell
how do cancer cells avoid immune destruction?
blocking of proteins that allow T cell to kill tumour cell
how do cancer cells enable replicative immortality?
in health, telomeres shorten so the cell dies
in cancer, the telomeres are not shortened so the cells replicate and don’t die
Give an example of a factor that interacts and promotes tumour growth?
interleukins
How do tumours metastasise?
- cells in epithelium break through basal lamina
- cells enter bloodstream
- cells divide to form tumour
- cells adhere to and penetrate the capillary wall
How do tumours induce angiogenesis?
angiogenic factors cause capillaries to sprout and build new blood vessels that supply the tumour with nutrients and oxygen
How are normal cells removed? e.g after DNA damage
apoptosis
What are proto-oncogenes and oncogenes?
Proto-oncogenes - normal cells that promote cell proliferation, survival and angiogenesis
Oncogenes - mutated versions/ increased expression of photo-oncogenes, causing increased/uncontrolled activity of expressed proteins
Are TSGs and proto-oncogenes dominant or recessive?
Proto-oncogenes - dominant
TSGs - recessive (so if there is a mutation in one allele, there is still normal cell division as there is still another functioning allele to compensate)
What are the differences between oncogenes and TSGs?
- In oncogenes, mutations in one of the two alleles is significant
- In TSGs, both alleles must be affected
- In oncogenes, gain of function of a protein that signals cell division
- In TSGs, loss of function of a protein
- oncogene mutations arise in somatic cells (are not inherited) whereas TSG mutations can be present in germ cells therefore inherited
What are some examples of oncogenes?
RAS, RAF, HER2, EGFR
What are 4 types of mechanisms of oncogene activation?
- translocation of an oncogene from a low to active transcription type
- point mutation - substitution of single base produces a hyperactive oncoprotein
- amplification - increased expression by insertion of multiple copies of an oncogene
- insertion - of a promotor near an oncogene
give examples of TSGs
APC, P53, RB, BRCA1, BRCA2, hMLH1, hMSH2
What are the two categories of TSGs?
- gate keepers/ anti-oncogenes - negative regulators of the cell cycle and proliferation and positive regulators of apoptosis
- caretakers - maintain genetic stability
a mutation in which TSG results in Li-Fraumeni syndrome?
p53
a mutation in which TSG results in familial adenomatous polyposis ?
APC
a mutation in which TSG results in HNPCC?
hMLH1, hMSH2
What is the minimum number of genetic alterations needed to transform a normal cell into a neoplastic cell?
3-6
What are the 3 locations that ovarian tumours can arise from?
- Surface epithelial tumours (90% of cases)
- Germ cell tumours - arise from the oocyte
- Sex chord stroma
What are the most common types of surface epithelial tumours?
- serous (tubal mucosa)
- mucinous (endocervical)
- endometroid (endometrium)
What does nulliparous mean?
Hasn’t given birth
What is serum Ca125 used for?
a tumour marker in ovarian cancer
What is a bilateral sapling-oophrectomy?
Removal of both ovaries
What are the 3 types of epithelial tumours?
- benign
- borderline - abnormal architecture but no evidence of invasion
- malignant - evidence of invasion
What prefix is used to describe tumours composed of glandular epithelium?
Adeno
How are benign ovarian epithelial tumours sub classified?
Based on components:
- Composed of cysts (cyst adenoma)
- Fibrous tissue (adenofibroma)
- Cystic and fibrous (cystadenofibroma)
Explain the nomenclature of ovarian malignant epithelial tumours
- cystadenocarcinoma = malignant ovarian epithelial tumour
- then classified by type of epithelium i.e serous cystadenocarcinoma
- then further classified into:
- high grade (aggressive), low grade (slower growing, less aggressive, better prognosis)
What is FIGO staging?
staging for ovarian cancer
what are non-specific symptoms of epithelial ovarian cancer?
- weight loss
- bloating
- fatigue
- urinary frequency
- sometimes PV bleeding
What are 3 protective factors of epithelial ovarian cancer?
- having children
- breast feeding
- contraceptive pill
What structures can a mature cystic teratoma contain?
hair, sebaceous material (hair follicles), teeth
Give 4 examples of germ cell tumours?
- teratomas (most common)
- yolk sac tumours
- embryonal carcinoma
- dysgerminomas
What is an immature teratoma?
malignant teratoma (only 1% of teratomas are malignant most are benign)
what is a mature cystic teratoma?
“tumour that contains elements of all three germ cell layers”:
- ectoderm e.g skin and hair
- mesoderm e.g muscle, bone, cartilage
- endoderm e.g respiratory epithelium, GI epithelium
What are dysgerminoma?
- malignant
- very rare
- sensitive to chemo
- LDH used as tumour marker
What are yolk sac tumours?
- malignant
- sensitive to chemo
- a-FP used as tumour marker
What are choriocarcinomas?
- extremely rare
- usually in placenta
- malignant
How do sex-cord stromal tumours arise?
arise from ovarian stroma that was derived from the sex cord of the embryogenic gonad
What are the 3 types of sex-cord stromal tumours?
- Thecoma / fibrothecoma/ fibroma
- benign
- thecomas and fibrothecomas produce estradiol - granulosa cell tumours
- low grade malignant, produces estradiol - Sertoli-leydig cell tumours
- produce androgens
What is meig’s syndrome?
triad of ovarian tumour (fibroma), right sided pleural effusion ascites
What is the most effective way of evaluating an ovarian mass?
pelvic ultrasound
Which serum markers do we use in ovarian neoplasms?
- Ca125
- a-FP, LDH, BHCG
What is a Krukenberg tumour?
metastatic tumour in the ovary that originates in the stomach
