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Cellulaire Oncologie > AMC-HC 7: Invasion & Metastasis > Flashcards

AMC-HC 7: Invasion & Metastasis Flashcards

13-02

1
Q

When are most tumors noticed?

A

When they start influencing the function of organs and tissues

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2
Q

Tumor metastasizing potential differs per tissue. Which cancer has a high risk for metastasis? And which have a lower risk?

A

Melanomas – high
Basal cell carcinomas of skin and astrocytomas – low

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3
Q

Stages of metastases

A

Intravasation
> Transport through cicrulation
> Arrest in microvessels of various organs
> Extravasation
> Formation micrometastasis
> Formation Macrometastasis

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4
Q

For carcinomas, the most common cancers, to invade, they need to break through the basement membrane. Which enzymes help them?

A

Proteases that cleave the ECM > malignant cells locally invade nearby tissues and gain access to growth factors and blood supply of the stromal niche

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5
Q

Which action increases the risk of metastasis enormously?

A

Breaking through the basement membrane

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6
Q

How do macrophages enable intravasation of cancer cells into the circulation?

A

They secrete EGF > stimulation intravasation

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7
Q

Why is the blood a hostile environment for cancer cells?

A

-No support from stroma cells
-No contact with other cells
-Hydrodynamic shear stress in vessels
-Not built for microcapillaries (they have large nuclei and do not fit well.

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8
Q

A readout for risk for metastasis (useful for therapy), is made by measuring …

A

Circulating tumor cells (CTCs)

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9
Q

What is a problem with measuring CTCs?

A

Complicated comparisons between cancers and patients

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10
Q

Detection of tumor DNA

A

Mutation profile: mutations and translocations

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11
Q

Most CTCs spend little time in cicrulation. Where do they end up? and can they escape this place?

A

They get stuck in the lung microcapillaries > but they can escape and get stuck nearby other organs in the systemic circuit and metastase there.

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12
Q

What characteristic of cancer cells is essential for metastasis?

A

Their size: they have to get stuck in microcapillaries to be able to invade

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13
Q

Mechanisms of extravasation by cancer cells

A

-Through the endothelium
-Growing within the vessel

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14
Q

When cancer cells escape from vessels, they enter a new environment with growth factors and new stroma cells et cetera. Does this have a positive or negative effect on the cancer cell?

A

Can be either positive or negative

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15
Q

Colonizing cancer cells first form micrometastases. From which number of micrometastasis, a macrometastase is formed?

A

There is no vast number > the chance of forming a macrometastasis is very low

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16
Q

Why is the chance of formation of micrometastasis very low?

A

The new environment is not compatible to a single cancer cells most of the times.

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17
Q

The incedence of micrometastases has a negative effect on the patients …

A

prognosis

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18
Q

Differences between initial micrometastases and secondary wave

A

-Initial micrometastases: generically distinct: cells can disseminate but not colonize > different mutagenic profiles (selection, only the best adapted cells will be able to form micrometastases and macro)
-Secondary wave: generically similar, derived from the primary metastasis which was adapted well to the colonization of new tissues.

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19
Q

Secondary wave of metastases is also called the …. and is responsible for the …

A

Metastatic shower > most deaths (faster growth because of better adaptation)

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20
Q

Micrometastases will die after a few days if they do not grow, true/false?

A

False: they can remain dormant for large periods of time > waiting for colonization

21
Q

Which transition enables invasion?

A

Epithelial-mesenchymal transition (EMT)

22
Q

What do carcinoma cells need to do to acquire motility and invasiveness?

A

-Shed epithelial phenotypes, detach from epithelial sheets
-Undergo the epithelial–mesenchymal transition (EMT)

23
Q

EMT is also required for normal healthy processes. Name one

A

Embryogenesis or wound healing response
> Carcinomas can thus activate the latent program which is usually confined to early embryogenesis and to damaged adult tissues!
> the TF’s for EMT induction are relevant

24
Q

EMT involves changing of shape, acquisition of motility and fundamental alterations in gene expression. Name EMT related gene regulations

A

-Downregulation of E-cadherin and cytokeratins (hallmarks of epithelial cells)
-Upregulation of vimentin (large intermediate filament component of the mesenchymal cell cytoskeleton)
-Twist gene > stimulates EMT: lower expression of epithelial markers E-cadherin, beta-catenin, and gamma-catenin and higher mesenchymal marker expression: fibronectin and vimentin

25
Q

E-cadherin role

A

Transmembrane protein: the extracellular domain functions as a hook which can links cells with E-cadherin to each other > the intracellular domains are tethered to the actin fibers of the cytoskeleton via an complex of alfa/beta-catenins. The actin cytoskeleton provides tensile strength.

26
Q

Loss of E-cadherin

A

Beta-catenin goes free into the cytosol and translocates to the nucleus to promote proliferation genes via binding to TF’s (Wnt signaling)
> also, connectivity between adjacent cells decreases.

27
Q

Which signaling is involved in EMT induction?

A

Paracrine / autocrine

28
Q

How can tumor associated macrophages promote EMT in cancer cells?

A

By secreting TNF-alfa or EGF

29
Q

Is EMT a reversible process?

A

Yes, after colonization, cancer cells can undergo a mesenchymal-epithelial transition (MET)

30
Q

EMT transcription factors can also induce a special state of cells. Which one?

A

Stem cell state: needed for cancer cells to grow and metastasize.
> EMT program can enable carcinoma cells to translocate from the core of primary tumor to foreign tissue during metastasis

31
Q

Why is stemness important for carcinoma cells?

A

It endows disseminating carcinoma cells to be able to form metastases and to grow.

32
Q

Why are extracellular proteases important for invasion?

A

Remodeling of nearby tissue > excavating passageways through ECM and breaking the basement membrane

33
Q

Which extracellular proteases excavate the ECM?

A

Matrix metalloproteinases (MMPs like MMP2)
> these proteases are secreted by macrophages, mast cells and fibroblasts.

34
Q

How is the activity of MMPs normally controlled?

A

By the secretion of inactive pro-enzymes but in cancer, the proteolysis is a continuous process.

35
Q

Which kind of expression of MMPs can drive carcinogenesis?

A

Ectopic expression of MMPs

36
Q

What is a marker of metastasis?

A

Cancer cell positive lymph nodes

37
Q

The site of metastasis has a certain risk per type of primary tumor. Which metastases mostly occur with prostate cancer? And with breast cancer?

A

Prostate: to bone marrow
Breast cancer: to lungs and bone marrow

38
Q

What is the affinity of different primary tumors /cancers towards a certain organs for metastasis called?

A

Tropisms to these organs

39
Q

Why do tropisms exist?

A

Because cancer cells are uniquely equipped for colonizing different sites (ability to colonize certain organs is rarely achieved)

40
Q

Seed and soil hypothesis

A

metastizing cancer cells (seeds) find compatible home only in certain hospitable tissues (soil)

41
Q

What is another factor (besides certain cancer being equipped better for metastasis in certain organs) for tropisms (preference for metastasis tissue)?

A

The layout of vessels and the route of cancer cells through the curculation

42
Q

What sites can attract certain cancer cells?

A

Sites of chronic inflammation > more blood flow towards the inflammation site > blood flow patterns may explain metastase patterns

43
Q

Tumor self-seeding

A

Tropism towards the site of the primary tumor

44
Q

Vascular ZIP code (adres) theory

A

receptors on the walls of capillaries attract circulating tumor cells

45
Q

Prediction of metastase sites:

A

66% (majority): blood flow patterns
20% specialized microenvironments of target tissues
14% by negative interactions > tissues actively repelling cancer cells

46
Q

Why do micrometastases reduce the long-term survival of patients?

A

-Dormant micrometastases are often non-cycling and thus resistant to therapy

47
Q

Why do immunosuppressed patients have explosive development of aggresive metastatic disease?

A

The immune system may suppress the growth of micrometastases

48
Q

What proves the genetic determinants of metastases?

A

Only a subpopulations of genetic diversity of primary tumor found in metastases, so selection-based

Cellulaire Oncologie (14 decks)

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