Cancer becomes a global problem because of its high mortality and morbidity. The higher mortality rate of cancer patients relatd to their metastasis capacity. This lecture will present recent advances in understanding of metastasis and cancer invasion.
Main steps of cancer metastasis start from angiogenesis of primary tumor. Then, several cancer cells will invade or detach vascular wall to enter circulation system. In this phase cancer cells form emboli, may interact with platelets or other component of blood. Heart pumps cancer cells containing blood into target organ. In target organ, cancer cells attach to vessel wall and extravasation. Cancer cells develop microenvironment to support their viabilty.
1. Tumor angiogenesis
Tumor angiogenesis is establisment of new blood vessels that penetrates into cancer tissue. This blood vessels are very important to supply nutrients and oxygen and remove waste products. Cancer cells release some signaling molecules to normal tissue which encourage growth of new blood vessels. The major mediator of angiogenesis is Vascular Endothelial Growth Factor A (VEGF A). VEGF A expression is stimulated by epigenetic (hypoxia, cytokines, growth factor, sex hormone and chemokines) and genetic factors. VEGF A bind to VEGF R1, VEGFR2 or NRF2 receptor. This binding activate PI3Kinase-Akt pathway to promote cell survival. VEGF A and VEGFR2 also activate some other pathways that support cancer cells capacity in migration, mobilization, proliferation and vascular permeability.
Some research investigated role of Endothelial-Cell–Associated Deltalike Ligand 4–Notch signaling pathway in angiogenesis. Dll4 binds to notch receptors that are expressed in the vascular endothelial cells composing the “stalk” component of a growing capillary sprout, adjacent to the tip cells. This result emphasize combination of anti-VEGF drug and DII4 targeting drug has better efficacy.
2. Invasion or metastasis properties
Cancer cells can detach vessel wall, firstly they will detach lymphatic vessel wall. Interconnection of lymphatic and blood vessels make cancer cells possible to enter circulatory system. Several mechanism promote metastasis properties of cancer cells.
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Adhesive capacity
Adhesive capacity
Cancer cells have less adhesive capacity of each other, thereby allows cancer cells to seperate from the main tumor mass. In many cases, loss of adhesiveness is corelated with E-cadherin decrease. E-cadherin is binding protein that binds epithelial cells one another.
- Epithelial Mesenchymal Transition (EMT)
EMT is character change of cancer cells which make them more invasive, from epithelial characters change to mesenchymal characters. E-cadherin is an important adhesion molecule that support adhesiveness. It connects adheren junction in cell surface and Cathenin protein in cytosol. Less E-cadherin will increase Beta cathenin intracytoplasmic. Free Beta cathenin bind some target genes, such as Myc, Cyclin, TCF-1, MMP etc. Activation of target genes lead to migration enhancement and adhesion reduction.
The importance of EMT stimulates researchers to find out transcription factors responsible for EMT.
Name | Where first identified | Type of transcription factor | Cancer association |
Slug | Determination of the neural crest and early mesoderm in chicken | C2H2 type zinc finger | Breast cancer lines; melanoma |
Snail | Mesoderm induction in drosophila/neural crest migration in vertebrates | C2H2 type zinc finger | Invasive ductal carcinoma |
Twist | Mesoderm induction in Drosophila; emigration from neural crest | bHLH | Invasive lobular carcinoma, high grade melanoma and neuroblastoma |
Biochemical analysis shows increase of mesenchymal-state proteins and decrease of epithelial-state protein. Some proteins that increase are: fibronectin, vimentin, N-catenin, and srn-actin. Proteins that decrease are: E-cadherin, alfa catenin, beta catenin and gamma catenin.
It is likely that EMT triggered by mixture of signals from stromal and intracellular (such as: ras oncogene). Combination of signals cause loss of epithelial adheren junctions and cellular polarity. In the other hand, combination of signals trigger cellular motility, invasiveness and protease secretion that support cancer metastasis.
- Cell Motility
Cellular motility is activated by signaling molecules. After the loss of cell-cell adhesion, cancer cells migrate to other place with guidance of these signaling molecules as chemoattractant.
- Secretion of proteases to degrade structures that limit cancer cells movement. One of important protease in cancer metastasis is plasmin proteases. Plasmin is converted from precursor plasminogen by converting enzyme, plasminogen activator. Plasminogen activation is catalyzed by urinary (uPA) or tissue-type Plasminogen Activator (tPA). uPA known as an important factor in cell migration and invasiveness, such as cancer metastasis. After plasminogen being activated to form plasmin, this protein can degrade basal lamina and extracellular matrix. Plasmins also activate matrix metalloproteinase by cutting of its tail.
3. Circulating cancer cells
Cancer cells may be deposited as homotypic clusters that lodge in narrow capillaries due to size restriction. Cancer cells also have capacity to form emboli, associated with platelets and leukocyte, form projection to enhace adhesive capacity to vessel wall. cancer cells-platelets emboli then adheres endothelial cells by interaction with L-selectin ligand. Interaction with endothelial cells initiate extravasation process into target organ
4. Target organ
Cancer cells have special affinity for microenvironment of target organ. Cancer cells ability to grow is related to molecules present in the target organs. Certain molecules are needed by cancer cells, so that some cancer cells have specific location to spread. For example, prostate cancer probably spread to brain, lung, bone marrow and liver.
Overview of novel findings in cancer metastases: VEGFC/VEGFR3
VEGFR3 and VEGFC interaction contribute in invasiveness of multiple cancer types. VEGFr3 is receptor that may influence cell migration and cell proliferation through multiple pathways: PI3Kinase, Src and PLC-gamma. VEGFC contributes as ligand that bind to VEGFR2. Their interaction also enhances metastases properties by lymphangiogenesis promotion through JNK1/2, AKT or ERK pathway.
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