Metastasis

What are the six requirements for successful metastasis?

(1) Digesting barriers to local tissue invasion (2) Moving (3) Finding an escape route via blood vessel, lymphatic vessels (4) Getting into the vessel and surviving in circulation (5) Arriving at destination and escaping blood vessel (6) Surviving and growing in new tissue

Steps of the Metastatic Cascade

(1) Primary tumor formation; (2) localized invasion; (3) intravasation and interaction with platelets, lymphocytes, and other blood components; (4) transport through circulation; (5) arrest in microvessels of various organs; (6) extravasation (leave blood vessel); (7) formation of a micro- then macrometastasis

Tamoxifen

A drug used as adjuvant therapy to prevent cancer recurrence.

Positive Lymph Node

A lymph node local to the site of the primary tumor that has been removed and found to hold tumor cells -- indicates that cells in the primary tumor have become metastatic.

Adjuvant Therapy

A preventative therapy given after initial surgical resection of localized cancer to prevent tumor recurrence and distant metastases. Includes chemotherapy, radiation, and target therapy. Will not cure cancer (except sometimes chemo does cool).

Cancer Immunotherapy

A therapy that harnesses a body's own immune cell to fight tumors, reactivating T-cells that were shut down via surface interactions by tumor cells -- a systemic therapy, only useful for tumors like melanoma that are susceptibile to immunologic attack

KIT

An enzyme that becomes oncogenically mutated in GIST (gastrointestinal stromal tumor) -- can be inhibited by Gleevec to relieve cancer symptoms but often grows resistant

Cytokeratin

An epithelial-specific marker that can be identified via immunostaining to find tumor cells in lymph nodes

Bone Marrow Aspirates

Analyzing these can help detect micrometstases

What cancers metastasize to the lung?

Breast, melanoma, renal-cell, colorectal, sarcoma

How do we treat metastases after they occur?

CHEMO.

Timeline of Lung Cancer Metastasis

Can infiltrate and colonize very early during the course of the disease

Circulating Tumor Cells (CTCs)

Cancer cells in the peripheral blood. Act as predictors of tumor progression. Can be detected by RT-PCR for epithelium-specific transcripts or immunopurification of epithelial cells from blood.

How to cancer cells carry out osteolytic metastasis?

Cancer cells secrete factors like PTHRP, activating osteoblasts that in turn release RANKL, promoting the differentiation of monocytes into osteoclasts. Osteoclasts degrade the bone matrix, while also releasing and activating latent growth factors like TGF-B that help tumor cells proliferate.

Tumor-Associated Macrophages

Cells that assist in the migration of metastatic cancer cells across collagen fibers from the primary tumor toward the blood vessel.

"Seed and Soil" Hypothesis

Describes the fact that tumors usually have a preference to metastasize to particular sites -- tumors can spread throughout blood stream but tend to proliferate only in specific new areas

Metastasis v. Primary Tumor Volume

Generally, the risk of developing clinically metastatic disease increases with the volume of the primary tumor.

Positive Margins

If tumors cells are found at the edge of the inked outline made during surgical removal, the tumor was not completely excised and has a high risk of recurrence/metastasis.

Negative Margins

If tumors cells are not found at the edge of the inked outline made during surgical removal, the tumor was completely excised and has a low risk of recurrence/metastasis.

Timeline of Breast Cancer Metastasis

Infiltration can take place very early but colonization may not occur until many years/decades later

What cancers metastasize to the liver?

Lung, breast, colorectal, pancreatic, stomach

What cancers metastasize to the brain?

Lung, breast, melanoma, renal-cell, colorectal

What cancers metastasize to the bone?

Lung, breast, renal-cell, colorectal, prostate

What cells are naturally motile?

Mesenchymal cells/fibroblasts

Two Major Types of Bone Metastasis

Osteolytic (bone is broken down, as in multiple myeloma and breast cancer) and osteoblastic (aberrant bone formation, as in prostate cancer) bone metastasis

Infiltration

Refers to the ability of cancer cells to access a distant organ

Colonization

Refers to the ability of infiltrated cancer cells to generate a substantial metastatic colony in the distant organ

Metastasis

Spread of cancer cells from the primary tumor to distant sites. Results in 90% of human cancer deaths. Cancers at distant sites retain the histology and characteristics of the primary tumor.

Timeline of Colorectal Cancer Metastasis

Take many years to become invasive but can then colonize right away

It is relatively easy for cancer cells to metastasize to...

The bone marrow. Because its sinusoids are fenestrated.

It is difficult for cancer cells too metastasize to...

The brain, due to the blood-brain barrier (continuous capillaries, endothelia, basement membrane, astrocytes)

Sentinel Node

The lymph node to which primary tumor cells are most likely to spread in metastatic -- usually dissected to determine whether metastasis has occurred. It is identified by injecting colored dye or radiolabeled in the primary tumor and seeing what lymph node is labeled most quickly.

Epithelial-to-Mesenchymal Transition (EMT)

The mechanism by which cancer cells move out of their primary tissue in order to metastasize. Often, epithelial cells (non-motile) lose their epithelial characteristics and acquire mesenchymal characteristics (motile). Wrt histology, the basement membrane disappears.

Mesenchymal-to-Epithelial

The mechanism through which the epithelial nature of a tumor is restored. This occurs once a tumor has metastasized to its new location. Wrt histology, the basement membrane reappears.

Macrophage/Carcinoma Cell Assay

The test cells are plated on the bottom of a culture dish and coated with a gel of extracellular matrix proteins (e.g. matrigel or collagen). Macrophages and cancer cells are labelled with different fluorescent colors. When either cell is plated alone, neither migrate. When plated together, cooperatively migrate.

How do metastatic tumor cells escape from the blood vessel?

They adhere to the basement membrane of a blood capillary, which provides survival signals to them. As the cancer cells replicate, they disrupt the capillary wall and invade into the surrounding tissue.

How do cancer cells digest barriers to local tissue invasion?

They utilize protease enzymes to degrade ECM, specifically the basement membrane. Cancer cells also adhere to one another using adhesion proteins like E-cadherin. Within the tumor microenvironment, there are lots of inactive growth factors that are activated upon protease cleavage.