lecture 5: tumor invasion and metastasis

primary tumor

the site where the malignant neoplasm arises

recurrence

tumor has come back after therapy

local recurrence

recurrence at primary site

regional recurrence

recurrence at draining lymph node

distal recurrence

recurrence at secondary site

CT, PET, scintigraphy

which types of imaging are often used to detect metastases?

90%

Among the people who die from cancer, ___ die from the effects of metastasis

rarely

do current therapies cure metastatic cancer?

basement membrane

the initial step of localized invasiveness is when in situ carcinoma breaches the _______

the entry of metastatic cells into the bloodstream

what is intravasation?

the leakage of metastatic cells from blood vessels into a surrounding tissue

what is extravasation?

colonization: it depends on the adaptation of the traveled cancer cells to the new microenvironment of the tissue

what is the final and most inefficient step of metastasis?

outward

For carcinomas, initial growth is ____ (path of least resistance)

outgrow its blood supply

since outward growth is self-limiting, the mass will . . . .

nutrients

Invasion is inevitable in the search for ____ and later leads to metastasis

no - limited mobility

except for mesenchymal or blood cells

Are most adult differentiated cells motile?

anchored (attached to basement membrane)

In the case of epithelial tissues, cells grow in ____ fashion

detached motile cells

Metastasis requires

an epithelial-mesenchymal transition (projectile spindle shaped morphology)

Mesenchymal invasion is initiated by . . .

proteases and integrins

what do cells express in mesenchymal invasion?

individual cancer cells detaching from the primary tumor

Amoeboid invasion is due to . . .

cells invade without losing contact with the primary tumor

During Coordinated invasion . . .

an intermediate of b and c: a clump of separated cells that travel together

what is a cohort invasion?

Epithelial to mesenchymal transition (EMT)

_______ transforms epithelia tumors into a fibroblast-like phenotype

cell invasiveness and cell–stroma interaction

EMT enhances ____ and _____

by single cells, often in a single-file alignment

how is mesenchymal invasion carried out?

the extracellular matrix is re-arranged

how do mesenchymal cells get a path for migration?

MET (mesenchymal to epithelial transition): allows the new cancer cells to become established

what process follows EMT?

they squeeze through gaps in it

what do amoeboid invasion cells do instead of re-forming the extracellular matrix?

chemokines (chemical signals)

what do amoeboid cells head toward?

amoeboid: it doesn’t rearrange the ECM

is amoeboid or mesenchymal invasion more energy efficient?

yes - front motile cells generate the path

does collective invasion re-shape the extracellular matrix?

still attached

in coordinated invasion, the invasive cells are ____ to the primary

multicellular sheet

the form of coordinated invasion looks like a

a migrating cluster of cells separate from the primary

cohort invasion looks like

invasive epithelial cancers

in what type of cancer is coordinated invasion observed in?

a subset of melanomas and in rhabdomyosarcomas

what type of cancers is cohort invasion observed in?

selectively attach to ECM and degrade it

what can leading path-generating cells in a cohort do?

epithelial tumor

which type of tumor is more likely to have collective invasion

individual invasion (amoeboid or mesenchymal)

Sarcomas, lymphomas, and leukemias are more likely to have ____

enter circulation

For a tumor to metastasize it must . . .

Paracellular – between cells
Transcellular – through cells

what are the two potential mechanisms of circulation?

lymphangiogenesis (formation of new lymph vessels)

Newer research has shown that tumors induce ______ which is correlated with metastasis

subclavian veins - entry into circulation

after first draining to regional lymph nodes (immune surveillance site), lymph systems will drain into

the bloodstream

Presence of cancer cells in ______ is a predictor of metastasis

tumor cells naturally release DNA fragments to surrounding fluids (blood, urine, CSF, etc)

how does circulating tumor DNA (ctDNA) appear?

0.25 (15 minutes) -3 hours

what is the half-life of ctDNA?

disease progression rather than diagnosis

ctDNA is best for evaluating . . .

only minutes (ill-suited for traveling)

how long do CTCs persist in circulation?

Tumor cell diameter ~ 20um

Capillary diameter ~ 8um

*Most cancer cells are likely stopped by physical blockages

how does cancer cell diameter compare to capillary diameter?

in the lungs

After entering circulation, where is the first capillary bed encountered?

extravasation: can twist out of blood vessels onto surrounding tissue

with the EMT-inducing transcription factor, “Twist,” what is enabled in cancer cells?

small clumps of disseminated cancer cells; often not detected clinically

what are micrometastases?

hundreds to thousands

Approximately 30% of breast cancer patients harbor _______ micrometastases in their bone marrow at time of presentation

half

how many of the patients with hundreds to thousands of micrometastases will develop metastatic disease?

many

Breast tumor cells can last dormant ____ after introduction into liver

yes

are dormant breast tumor cells resistant to chemotherapy?

Growth of microscopic into macroscopic metastases

what is colonization?

Just because a tumor cell reaches a distant site does not mean that it will thrive there

What does Paget’s seed and soil hypothesis mean?

different

one breast cancer cell that metastasized to the lung, and one the metastasized to the liver are genetically _____

1) Fewer phenotypic changes needed for colonization in certain organs (seed and soil hypothesis)

2) Layout of the vasculature (where veins take the cells first)

What are the two main reasons that cancer cells would prefer certain sites?

normal breast cells secrete protein to break down bones for milk calcium.

this normal process is utilized by breast cancer bone metastasis to break down bone

why does breast cancer commonly exhibit bone metastasis?

~3-5%

metastases with an unknown primary accounts for ___ of cancer cases in both sexes

lung and pancreas

which two cancers are the most frequent primary sites found at autopsy?

~75-85%

Primary can be figured out via gene expression in ___ of cases

1. Localized invasion
2. Intravasation
3. Travel through circulation
4. Arrest in organs
5. Extravasation
6. Formation of micrometastases
7. Formation of macrometastases

can you list the 7 steps of the metastatic cascade?