Cancer

Cancer, or malignant tumor, differs from benign tumors in two important aspects:

1. Cancer cells can divide and proliferate without control.
2. Cancer cells can invade neighboring or distant tissues, forming a secondary tumor.  The original tumor is called primary tumor.  The spread of cancer is known as metastasis.

Most malignant tumors originate from epithelial cells that line the surface of an organ or the body.  This type of tumors are called carcinoma. Another type, called sarcoma, originates from connective tissues such as bone, muscle and blood vessels.

Abnormal cell division

Normally, cell division is triggered by growth stimulatory signals that induce the expression of cyclin D1 and other proteins involved in the progression of cell cycle from G₁ to S phase. For example, binding of epidermal growth factor (EGF) to its receptor induces the expression of c-Fos via the Ras-Raf-MEK-MAPK pathway (illustration). c-Fos is a component of the transcription factor AP-1 that regulates the expression of cyclin D1 and many proteins involved in DNA synthesis. Abnormal cell division may result if any gene involved in this process has been mutated. Important examples:

p53
p53 plays a central role at the cell cycle checkpoint to ensure replication of correct DNA. Defective p53 would allow daughter cells to contain incorrect DNA.

pRB
pRB regulates the activity of E2F, which controls the expression of many proteins involved in DNA synthesis.

Ras
Ras is involved in the signaling pathway for cell growth. Its active state is normally inactivated by rapid GTP hydrolysis. However, a mutated form cause Ras to remain in the active state for a much longer period. 

EGFR
EGFR, also called ErbB, is the receptor for epidermal growth factor and its related peptide such as TGFa.  Its mutated form, EGFRvIII, is activated even in the absence of ligand binding (reference).

More Cancer-associated Genes

Mechanisms of metastasis

Epithelial cells are separated from other tissues by basal lamina (basement membrane) which is a kind of extracellular matrix (ECM).  They are normally well connected.  Epithelial cells are attached to each other by the molecular complex of E-cadherin and catenin, while integrin is responsible for the binding between epithelial cell and ECM.  Metastasis begins with the loss of these adhesion molecules and the activation of proteolytic enzymes such as plasmin and matrix metalloproteases (MMPs) that can degrade ECM, These enable transformed cells to penetrate ECM, enter blood or lymphatic vessels, and circulate to a distant location. 

Review articles:

• Harnessing the immune system to treat cancerr - J. Clin. Invest., 2007.
• S100A4, a Mediator of Metastasis - J. Biol. Chem., 2006.
• Recent insights into the role of Notch signaling in tumorigenesis - Blood, 2006.
• Akt Signaling and Cancer: Surviving but not Moving On - Cancer Research, 2006.
• Inflammation, a Key Event in Cancer Development - Molecular Cancer Research , 2006.
• Caveolin-1 in oncogenic transformation, cancer, and metastasis - Am. J. Physiol., 2005.
• Signaling Intricacies Take Center Stage in Cancer Cells - Cancer Research, 2005.
• Modeling metastasis in vivo - Carcinogenesis, 2005.
• Proteases, Extracellular Matrix, and Cancer - Am. J. Pathology, 2004.
• The Proteasome as a Target for Cancer Therapy - Clinical Cancer Research, 2003.
• Clinical, Cellular, and Molecular Aspects of Cancer Invasion - Physiol. Review, 2003.
• Cell adhesion molecule-mediated signalling during tumour progression - EMBO J., 2003.
• Integrins in invasive growth - J. Clin. Invest., 2002.
• Integrins in Cancer Cell Invasion - Eurekah Bioscience, 2002.
• The cadherin-catenin adhesion system in signaling and cancer - J. Clin. Invest., 2002.
• The Plasminogen Activation System in Cell Invasion - Eurekah Bioscience, 2002.
• Regulation of matrix metalloproteinase expression in tumor invasion - FASEB J., 1999.