Pathology 5 - Tumor Spread

Front 1

what is invasion?

Back 1

derangement of tissue sorting & violation of tissue boundaries

Front 2

(1) what is a normal invasion? (2) what is an abnormal invasion?

Back 2

neovascularization and wound healing

Hint 2

uses same signals but tumor invasion persists

Front 3

(1)what prevents invasion from occuring? (2) what occurs in malignancies?

Back 3

suppression by basement membrane and cell-cell communication

Hint 3

cross talk between epithelium and mesenchyme becomes abnormal

Front 4

what feature of tumors enables metastasis to occur?

Back 4

tumor heterogeneity

Front 5

what is a major feature that differentiates invasion from metastasis?

Back 5

invasion = contiguous sites, matastasis = noncontinguous sites

Front 6

what is required for metastasis to develop?

Back 6

a mass must generate cells with the ability to disseminate and form new foci of growth at noncontiguous sites

Front 7

(1) do all malignancies metastasize? (2) do all benign tumors metastasize?

Back 7

no

Hint 7

none

Front 8

what is the major cause of morbidity and mortality?

Back 8

metastasis

Front 9

what is metastisis in considering treatment?

Back 9

a key issue

Front 10

what tumors rarely metastasize?

Back 10

primary central nervous system tumors & intraocular tumors

Front 11

what are the pathways of metastasis?

Back 11

transcoelemic, lymphatic, hematogenous

Front 12

(1) what is transcoelomic metastasis? (2) how does it occur?

Back 12

tumor leaves original mass and spreading into a body cavity (can be any body cavity)

Hint 12

carcinomatosis or mechanical implantation (accidental or experimental)

Front 13

(1) what is carcinomatosis? (2) what is mechanical implantation?

Back 13

seeding of the body cavity; any body cavity affected by penetrating tumors, leaving the original mass and spreading into a body cavity

Hint 13

iatrogenic; trail of tumor cells through surgical line

Front 14

(1)what is lymphatic metastasis? (2) what type of malignancy has lymphatic metastasis?

Back 14

follows the direct pathyway of lymphatic drainage, including thoracic duct, but can also include skip metastases (skip local node but found in next node)

Hint 14

most common route for carcinomas (but sarcomas can use it as well), example: canine mammary carcinoma tumors (cranial mammary glands > nodes of cranial thorax > axillary nodes)

Front 15

(1) are big lymph nodes always a sign of metastasis? (2) what affects lymph nodes?

Back 15

no, maybe reactive

Hint 15

necrosis, inflammation of tumor mass, drainage

Front 16

Describe the appearnance when superficial subpleural lympatics are involved?

Back 16

a 'frosting' appearance

Front 17

(1) what is hematogenous metastasis? (2) what type of malignancy has hematogenous metastasis?

Back 17

follows the circulatory pathways, with preference to the venous system over the arterial system (elastin); first capillary theory and receptor driven site selection

Hint 17

typical of sarcomas (but carcinomas can use it as well),

Front 18

(1) what is 'first capillary bed' theory? (2) what is receptor driven site selection?

Back 18

mets to 1st capillary bed encountered; ie venous system to lungs and GI system to liver

Hint 18

metastasis depends on chemokine profile of different organs (chemokines bind receptors on tumor cells > tell cell to migrate > follows gradient, tumor cell binds receptor on endothelial cell > exporred through endothelium > metastasis, liver makes lots of chemokines > tumor cells attracted to liver)

Front 19

what are preferred organs for hematogenous metastasis?

Back 19

prostastatic > spine, thyroid > vessels, phyeochromocytomas > local veins

Front 20

what is the process leading to metastasis?

Back 20

transformed cell expands > cells within mass develop heterogeneity > clone of cells with the ability to metastasize emerges

Front 21

what are the mechanisms of metastasis?

Front 22

what occurs during detachment?

Back 22

down regulation of cadherins reducing cell to cell attachment and permitting greater cell mobility

Front 23

(1) what occurs during adhesion? (2) how is this related to metastic success?

Back 23

Metastatic cells tend to have more attachment molecules (integrins, laminin receptors, others) which are found all over the cell rather than on the basal aspect to adhere to basement membranes components (fibronectin, laminin, collagen IV) than normal cells

Hint 23

the number of receptors that aid in attachment determine the success of metastasis

Front 24

(1) what is the effect of closer attachment? (2) what role do fibronectin receptors play?

Back 24

smaller amount of enzymes digest more efficiently

Hint 24

required for metastasis (block fibronectin receptors results in no mets in melanoma)

Front 25

(1) what is required to initiate invasion? What are the most important proteases involved?

Back 25

digestion of extracellula matrix and basement membrane via proteases from neoplastic cells

Hint 25

matrix metalloproteinases (MMPs or type IV collagenase) activity has a strong association with metastasis and adjacent normal cells may be induced to produce MMPs by tumor cells

Front 26

(1) describe the basics of invasion by epithelial malignant cells? (2) what is the action of metalloproteinases?

Back 26

detachment through loosening of epithelial attachments > attach to basement membrane > degradation of basement membrane by proteolytic enzymes > tumor cell migration

Hint 26

MMP cleaves type IV collagen (dissolved basement membrane) but may be blocked by type IV collagenases and TIMP (tissue inhibitors of metalloproteinases)

Front 27

(1) what occurs during detachment? (2) what are the phases of invasion?

Back 27

down regulation of cadherins reducing cell to cell attachment (loosening of intercellular junctions) and permitting greater cell mobility

Hint 27

attachment, degradation/digestion, locomotion/migration

Front 28

(1) what occurs during migration? (2) what occurs during attachment?

Back 28

cell movement is stimulated by cytokines and growth factors in the basement membrane and extracellular matrix (released by digestion via the tumor cells for tumor growth) > fragment of proteins are cleaved by tumor proteases which are chemotactic for some tumor cells > the cleavage producs are chemotactic, growth promoting, and angiogenic functions (including vascular endothelial growth factor (VEGF) and basic fibroblastic growth factor (bFGF)

Hint 28

normal attachment to basement membranes via integrins and laminin receptors, which metastatic cells end to have more attachment molecules

Front 29

(1) what occurs in vascular penetration? (2) what occurs in tumo emboli?

Back 29

entry into blood vessels may occur between or through endothelial cells (reverse process from invasion/digestion); lympatics used preferentially because no basement membrane in lymphatics. Intravascular location exposes tumor cells to intense immune response attack (NK cells are most important)

Hint 29

tumor cell aggregation are protected from the immune responsed due to fibrin and platelets clumping with tumor cells (or tumor cells clumped with each other) and protecting tumor cells from the immune response (single cells are very susceptible to immune system due to tumor associated AG on surface)

Front 30

(1) how does homing and arrest occur?

Back 30

endothelial attachment and specific organ metastasis is receptor driven, laminin receptors facilitate attachment to the basement membrane more effectively facilitating metastasis up to 10x

Front 31

(1) what directs tumor cells to have tissue predilections? (2) give examples and normal activity

Back 31

chemokines which are structurally and functionally similar to growth hormones and bind receptors linked to G proteins

Hint 31

normally make white cells bind endothelium and migrate towards chemokine. CXCL12 and CXCR4 are important in tumors (anticancer therapy may block chemokines or receptors)

Front 32

what is extravasion?

Back 32

tumor cells penetrate blood or lymph vessels and move into interstitial area (reverse of initial process > new colony)

Front 33

(1) what is the site predilection of mammary carcinoma? (2) what is the site predilection of prostate cardinoma?

Back 33

lung, brain

Hint 33

lumbar lymph nodes

Front 34

(1) what is the site predilection of osteosarcoma? (2) what is the site predilection of hemangiosarcoma?

Back 34

lung

Hint 34

lung, liver

Front 35

what are 3 theories about chemokines in metastasis?

Back 35

fertile soil theory, endothelial addresss theory, chemo-attraction theory

Front 36

(1) what is the fertile soil theory? (2) What is the endothlial address theory?

Back 36

tumor cells need the appropriate grwoth facts at site of mets

Hint 36

tumor cells find site-specific receptors on endothelium

Front 37

(1) what is the chemo-attraction theory?

Back 37

tumor cells follow gradient of soluble substances

Front 38

(1) what must a metastasis do to be successful? (2) how frequent is metastasis?

Back 38

avoid host defences, establish adequate nutrition and waste elimination

Hint 38

<0.01% of cells in circulation give rise to metastasis, 1x10^9 cells may be shed from a tumor, therapy like cadherin E may be used to suppress metastasis