Quiz 5 Material [Tumor Invasion and Metastasis]

What are some functions of protein cleavage products that are generated when tumor cells digest the ECM?

- Function as growth factors for tumor cells - Promote angiogenesis - Function as chemoattractants that promote travel of tumor cells through ECM

List the steps of cancerous invasion of the ECM.

1. Dissociation of cells from one another 2. Attachment of tumor cells to ECM proteins 3. Degradation of ECM by proteolytic enzymes 4. Migration of tumor cells through digested ECM channels to blood or lymphatics

Through what mechanisms do tumor cells degrade ECM proteins?

1. Proteolytic enzymes secreted by tumor cells and cells unique to ECM (e.g. macrophages, fibroblasts) 2. Enzymatic digestion of ECM proteins creates channels for tumor cells to migrate through 3. Protein cleavage products are generated which may aid in metastasis

List the steps of cancerous vascular dissemination.

1. Tumor cells invade through vessel wall via proteolytic enzymes 2. Once in bloodstream, tumor cells aggregate into small clumps of tumor cells + platelets (may enhance survival and implantability) 3. Tumor embolus flows downstream and ultimately adheres to endothelial cell membranes at a distant site 4. Tumor cells burrow through basement membrane of vessel (via adhesion molecules, adhesive glycoproteins, proteolytic enzymes, etc) 5. Tumor cells enter into tissue that is discontinuous with primary tumor mass => proliferate, develop vascular supply, evade host defenses

What percentage of newly diagnosed solid cancer patients, with the exception of BCC patients, present with metastases?

30%

What factors govern cancerous homing?

Anatomic considerations - tumor cells will follow natural pathway of drainage - Lymphatic embolus goes to nearest downstream lymph node - Vascular embolus goes to nearest downstream organ that the vein drains into Heterogeneity of tumor cell adhesion molecules & ligand molecules on endothelial cells - determines what tumor cell can attach to what endothelial cell(s), and thus initiate implantation Specific chemokine receptors on cancer cell membranes will lead them to tissues with HIGH CONCENTRATIONS of the CORRESPONDING chemokines - e.g. Breast cancer cells that express chemokine receptors CXCR4 and CCR7 will metastasize to tissues that have high concentrations of chemokines which bind to those receptors Unpermissive environment of some tissues (e.g. skeletal muscle) makes them naturally impervious to metastasis

Describe the spread of cancer through lymphatics.

Cancer cells invade into lymphatic vessel and travel via multiple AFFERENT vessels to the nearest downstream lymph node, where they divide. Cancer cells exit node via single EFFERENT lymphatic vessel and spread to more distant nodes within various areas of the body.

What are the three major proteolytic enzymes used by tumor cells to degrade the ECM?

Cathepsin D Urokinase plasminogen activator Matrix metalloproteinases - digest collagens within ECM

Through what mechanisms do tumor cells dissociate from one another?

Down-regulation of E-cadherins on tumor cell membranes prevents the molecules' ability to adhere to other cells Mutation within the cancer cell in genes for catenins - Catenins link E-cadherins to cell's cytoskeleton, so a defect in catenins would reduce the ability of E-cadherins to bind to other cells

What is the most common route for SARCOMA metastasis?

Hematogenous spread, most commonly through veins

What are the two phases of metastasis?

Invasion of extracellular matrix Vascular dissemination and homing

What are the most commonly involved sites for hematogenous spread? Why?

Lungs - all venous blood flow drains to SVC/IVC, then into RA -> RV -> lungs Liver - Portal vein receives blood from colon, pancreas, esophagus, and stomach venous drainage, all of which are highly predisposed to cancer

What is the most common route of CARCINOMA metastasis?

Lymphatic spread

Name two cancers that can invade but not metastasize.

Malignant glioma of CNS Basal Cell Carcinoma (BCC) of skin

Name a cancer that metastasizes rapidly but is not easily visible.

Malignant melanoma - small lump on skin, but many metastases

How can cancer seed body cavities and surfaces?

Malignant neoplasm invades through organ, and cancer cells enter open space such as the peritoneal cavity, pelvic cavity, pericardial cavity, joint spaces, etc. The cancer cells then implant, or seed, themselves on the surfaces of membranes, organs, and tissues within the space.

Define homing.

Movement of tumor embolus to final destination

Through what mechanisms do tumor cells attach to ECM proteins? What makes them very good at doing this?

Receptors on tumor cell membranes (e.g. integrins) bind to basement membrane proteins: - Adhesive glycoproteins: laminin, fibronectin - Collagen Tumor cells may have many more integrin (esp. laminin) receptors on their membrane vs. normal cells. May also contain types of integrins not found on normal cells. Degraded ECM proteins may generate novel ECM sites that bind to receptors on tumor cells.

List three main routes of spread for cancer.

Seeding of body cavities and surfaces Lymphatic spread Hematogenous spread

What is a general rule for likelihood of metastasis?

The larger and more rapidly growing the primary neoplasm, the more likely for metastasis. There are some exceptions to this rule. Metastasis also reduces the possibility of cure.

What is an advantage of cancer commonly using lymphatics to spread? Give an example.

The pattern of lymph node involvement is usually but not always, predictable in that it follows the natural route of lymphatic drainage. E.g. Cancer of the upper outer quadrant of the breast (common location for cancer) will typically metastasize into the axillary nodes, which is the first site of lymphatic drainage for that region of breast tissue.

What is the difference between tumor invasion and metastasis? Give examples.

Tumor invasion refers to malignant cancer that breaks through its tissue of origin to invade the surrounding tissue. An example would be cancer of the bone that penetrates into the surrounding muscle and fat. Tumor metastasis refers to a piece of the primary malignant tumor that breaks off, enters circulation, and then deposits elsewhere in the body, where it forms new tumor(s).

What is significant about malignant tumors interacting with the ECM?

Tumors and ECM components (e.g. fibroblasts, protein cleavage products) interact. Successful cancers are able to manipulate and utilize the ECM components, including stromal cells such as fibroblasts and inflammatory cells, to their advantage.