Cancer C

Cancer Cell Metastasis

-85% of cancer related mortality is a result of metastasis -Cancers spread through the blood or lymphatic systems -Metastasis is a complex and multistage process.

MLH1 and MSH2 gene mutation-related Hereditary Nonpolyposis Colorectal Cancer (HNPCC)

-Account for 5% of colorectal cancer. -Mean onset age 45 -Autosomal dominant -Normal MLH and MSH genes are involved in DNA mismatch repair

BRCA1 and BRCA2 gene mutations

-Accounts for 5-10% of breast cancers ad ovarian cancers. -Autosomal dominant -Normal BRCA1 and 2 are tumor suppressor genes, encoding proteins involved in DNA damage repair ->1,000 different mutations

Intravasation: Gaining access to circulation 2

-Adhesion to basement membrane through increased surface expression of certain CAMs for basement membrane proteins, e.g. certain integrins and slectins

Cancer Cell Invasion and Metastasis: Survival in the blood stream 3

-Cancer cells can interact with platelets through increased surface expression of receptors such as integrins to cause their aggregation to form a thrombus to evade immune surveillance

Cancer Cell Invasion and Metastasis: Extravasation; getting through the vasculature again and settling down 2

-Cancer cells establish a new growth of tumor mass and induce angiogenesis to form new vasculatures, forming a metastasis

Cancer Cell Invasion and Metastasis: Extravasation; getting through the vasculature again and settling down 1

-Cancer cells induce endothelial cell retraction, produce MMPs and cathepsins to digest subendothelial matrix (SEM) proteins, and migrate into the sub-endothelial space

Cancer Cell Invasion and Metastasis: Survival in the blood stream 1

-Cancer cells that enter the bloodstream encounter the body's immune cells which most likely recognize them as foreign and would attack them.

Routes of Metastasis: Lymphatic spread

-Commonly observed for melanomas, carcinomas of the lung and breast. -Cancer cells first enter lymph nodes that receive drainage from the site of tumor. -They can spread to distal lymph nodes, and gain access to the vasculature through thoracic ducts (collects most of the lymph fluid in the body; drains into blood circulation at the brochiocephalic vein between subclavian vein and internal jugular vein.

Routes of Metastasis: Hematogenic spread

-Commonly observed for sarcomas of soft tissues. -Cancer cells can enter vasculature through peripheral vein that drains the site of the tumor locally, or through infiltrating cells

Intravasation: Gaining access to circulation 1

-Detachment from main tumor mass through rearranged cell surface cell adhesion molecule (CAM) exprescsion to reduce cell-cell contact; e.g. reduced expression of E-cadherin.

Proto-oncogenes

-Encode for proteins that are important in regulating cell growth and differentiation. -Certain mutations in photo-oncogenes or over-expression turn them into oncogenes resulting in over production of the gene product leading to tumor formation

WNT

-Encodes a family of secreted proteins that bind to G-protein linked Frizzled family cell surface receptor complex to free up cytoplasmic beta-catenin that then enters the nucleus, initiates transcriptional activity critical for cell proliferation. -Availability of WNT is regulated by binding SFRP-1 (secreted frizzled-related protein-1) -Loss of SFRP-1 is frequently observed in bladder cancers (38%), breast cancer (48%) and colorectal cancer (76%) -WNT also plays important roles in stem cell differentiation and is thought to contribute to cancer stem cell generation.

RAS

-First isolated from a rat sarcoma caused by a virus -Encodes a GTPase that plays an important role in signaling pathways mediating cell growth, differentiation and survival. -Proto-oncogenes HRAS and KRAS (Harvey and Kristen sarcoma) and NRAS (neuroblastoma) are found in 20-30% of human tumors. Mutations such as GGG (Glycine) to GTC (Valine) render RAS constitutively active and enables tumor formation.

Identifying a metastatic tumor

-Histological: Resemblance to the cells in the tissue of origin -Immunological: antigenic profile

Intravasation: Gaining access to circulation 3

-Locally degrade basement membrane proteins through the scretion of enzymes including matrix metalloproteases (MMP) such as collogenases and lysosomal proteases such as cathepsins

Common sites of metastasis of primary solid cancers

-Lung cancer: brain and bones -Colon cancer: liver -Prostate cancer: bones -Breast cancer: bones, lungs, liver, brain

Potential factors influencing sites of metastasis:

-Lymph or vasculature drainage -Local environment suitability: availability of specific growth factors, cytokines that facilitate secondary tumor growth

Cancer Cell Invasion and Metastasis: Survival in the blood stream 2

-One in 10,000 cancer cells that enter the blood stream may survive

Routes of Metastasis: Across body cavities

-Peritoneal cavity: Space between the parietal peritonium (attached to the abdominal wall) and visceral peritonium (wrapped around organs). -Pleural cavity: Around lungs -Pericardial cavity: Around the eart -Subarachnoid space in the brain -Joints

Routes of Metastasis: Mechanical Transfer

-Rare -Cancer cells may be accidentally transferred during operation or diagnostic procedures.

APC gene mutation-related familial adenomatous polyposis (FAP):

-Rare (1/30,000) -develop numerous colon polyps by age 20 that develop into colon cancer by age 40 -Autosomal dominant -Normal APC (adenomatous polyposis coli) gene is a tumor suppressor gene and the encoded protein helps targeting beta-catenin for ubiquitination hence preventing beta-catenin from entering the nucleus to initiate transcriptional activity for cell proliferation and migration.

Genes and Cancer: Oncogenes

-Small fraction of cancers are directly associated with specific gene mutations. -Most cases of cancer are sporadic. However various gene mutations contribute to tumorigenesis, but there are very fer times that a specific gene mutation can result in a specific cancer formation

Cancer Cell Invasion and Metastasis: Survival in the blood stream 4

-Thrombosis allows cancer cells to come to a stop against the flowing force of the blood stream to "settle"down. -Increased adhesiveness (also through integrin surface upregulation) to and spreading over endothelium ensures a full stop

Intravasation: Gaining access to circulation 4

-Tumor cells secrete factors to induce retraction of endothelial cell lining and actively move through the gap to gain access to the blood stream.

HRAS mutations

-high in bladder cancer

KRAS mutations

-high in leukemias, colon cancer, pancreatic cancer and lung cancer

Metastatic cancers can be detected before or after the discovery of primary tumor

True

Occasionally, a metastatic cancer is detected and primary tumor can not be found

True