Download Cell Biology of Cancer

Cell Biology of Cancer
Lecture Outline
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Introduction
Benign Growths vs. Malignant Tumours
Benign Growths
Malignant Tumours
Tissue Culture: Normal vs. Malignant Cells
Changes in Cancer Cells
Transformed cells
Changes in Glycoproteins are Associated with Cancer
Tumour Development
Metastasis: The Formation of Secondary Tumours
Some Details of Events of Metastasis
Matrix Metalloproteinases (MMPs) & ECM Digestion
Introduction
Oncogenes are genes that encode proteins that transform normal cells into malignant cells. Cells have protooncogenes that encode proteins required for normal cell function. These proto-oncogenes mainly function in
the regulation of the cell cycle and the control of cell growth. The conversion of a proto-oncogene to an
oncogene can occur in many different ways and typically is a multi-step process driven by carcinogens,
chemical or physical agents that cause cancer.
RNA tumour viruses contain oncogenes as part of their genomes. They introduce the oncogene into human
cells when they infect them. The proteins encoded by oncogenes include growth factors and their receptors
and their intracellular effectors such as Src, Ras and Raf. In fact mutated Ras is the most common oncogene
product found in human tumors. Many transcription factors are encoded in oncogenes as are proteins, such as
some cyclins, that regulate the cell cycle. Proteins that affect apoptosis (e.g., Bcl-2 of the mitochondrion) are
also encoded by oncogenes.
In this and the next lecture we will examine some aspects of cancer cells by focusing on topics that have
previously been covered in the course. For example, angiogenesis, a current area of strong interest in cancer
research is not covered due to time constraints.
Benign Growths vs. Malignant Tumours
Benign growths and cancers (malignant tumors) are not the same thing. As the points below indicate, benign
tumours are generally not life threatening while malignant tumours typically are.
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Benign Growths
• Encapsulated
• Non-invasive
• Limited growth
• Doesn't metastasize
• Rarely lethal
Malignant Tumours
• Not-encapsulated
• Invasive
• Uncontrolled growth
• May metastasize
• Often lethal
Tissue Culture: Normal vs. Malignant Cells
The growth of normal and transformed cells in culture reflects the differences between them.
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Normal cells
• Normal cells show "Contact Inhibition" of growth & of cell division
• When they make contact, they stop moving and then move off in the opposite direction; until they contact
another cell; once they are surrounded on all sides, they stop moving completely
• Contact also inhibits cell division, so once a cell is surrounded by other cells, it stops dividing
• These behaviours result in the formation of a monolayer or pavement of cells
Transformed cells
• Transformed cells are normal cells that have been changed into cancer cells (e.g., by oncogenes, radiation
or some other cause)
• Transformed cells show "no Contact Inhibition"
• When they come into contact, they crawl over each other
• Regardless of how many cells are in the culture, they keep dividing
• These behaviours result in the formation of mounds of cells.
Changes in Glycoproteins Associated with Cancer
As expected, contact inhibition is in part regulated by cell surface molecules.
• Cancers show altered surface glycoproteins
• Many cancers show elevated extracellular levels of beta-glucosidase and protease
• Treat normal culture cells with either of these enzymes: cells round up and begin to divide
• Remove enzymes and cells return to normal: stop dividing and form pavement
• Cancer cells often have low fibronectin (FN) levels; add exogenous FN & cells flatten, stop dividing
Tumour Development
A tumour is a heterogeneous mass of cells, derived from a single ancestral cell. Exposure to carcinogens
leads to the transformation of a normal cell into one with a cancerous phenotype. As this transformed cell
divides successively, some of the cells are changed further by various factors, leading to subclones which
differ from the original transformed cell. Some of the cells are non-viable and die. As the tumour grows it
becomes complex of clones of cells, each with different behaviours. Thus with time, it becomes increasingly
difficult to kill all the cells with drugs (e.g., tamoxifen for breast cancer) because each group can respond
differently to the treatment.
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Metastasis: The Formation of Secondary Tumours
Cells in an invasive tumour can separate off, digest a pathway through the extracellular matrix and enter the
bloodstream. When they reach a permissible site, they can exit (extravasation) the blood stream and set up
shop as secondary tumours (metastases).
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Some Details of Events of Metastasis
1.Detachment from the primary site
o Mutations in cell-to-cell adhesion (homotypic binding)
o E.g. loss of E-cadherin expression
o Individual tumour cells break loose from primary mass
2.Invasion into circulatory vessel
o Cells must penetrate basement membrane (heterotypic binding) and degrade ECM
o Secrete high levels of extracellular proteases including matrix metalloproteinases (MMPs)
o Cells must penetrate basement membrane of circulatory vessel
o Involves heterotypic binding via integrin and laminin receptors
3.Mobility through circulatory system
o Mobile cells vulnerable in blood stream
o 1 in 10,000 survive
4.Establishment of a new colony
o Most common site of distant metastases are lungs or liver
o Some cancers show organ preference
o Local concentrations of growth factors and hormones
Matrix Metalloproteinases (MMPs) & ECM Digestion
Recently a lot of research has focused on matrix metalloproteinases (MMPs) as targets for the development
of anti-cancer drugs. For metastasis to occur, the cancer cell must be able to leave the original tumour. This
requires that it penetrate through various types of extracellular matrices. The basal lamina are dense, highly
organized extracellular matrix structures. Some cancer cells secrete MMPs but in most cases the cancer cells
induce local normal cells to secrete MMPs. Either way, the MMPs digest the protein and proteoglycan
components of the basal lamina making a hole through which the cancer cell can move. Drugs that inhibit
MMPs, prevent this digestion and the ability of the cancer cell to migrate out of the tumour.
MMPs have also been implicated in arthritis, multiple sclerosis and atherosclerosis and tooth decay.
©Copyright 1998-2009 Danton H. O'Day
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