Mechanisms of Tumor Development

Multistage Carcinogenesis:

Tumors consist of cells whose growth and morphological characteristics are markedly different from those of normal cells. Criteria for malignancy include increased cell proliferation, loss of differentiation, infiltrative growth, and metastisis to other organs.

Malignant transformation is a multi stage process, typically a progression from benign lesions (e.g. adenoma) to malignant tumors (e.g. carcinoma). The evolution of malignant cells is caused by the sequential accumulation of alterations in genes responsible for the control of cellular proliferation, cell death, and the maintenance of genetic integrity.

The development of cancer may be initiated by environmental agents (chemical carcinogens, radiation, viruses) and inherited genetic factors (germline mutations).

Carcinogen Activation and DNA Repair:

Many chemical carcinogens require spontaneous or enzymatic activation to produce reactive intermediates which bind to DNA. The resulting carcinogen-DNA adducts may be eliminated from DNA by various enzyme-mediated repair processes.

In cells and tissues with deficient DNA repair, replication of carcinogen-damaged DNA may result in the mutation of genes that regulate cell growth and differentiation in target cell populations. Such genetic alterations typically lead to progressive genetic instability resulting in uncontrolled growth, loss of differentiation, invasion, and metastasis.

A comprehensive listing of human DNA repair genes: http://www.sciencemag.org/cgi/content/abstract/291/5507/1284

DNA Repair Interest Group (NCI): http://www.nih.gov:80/sigs/dna-rep/

Oncogenes and Tumor Suppressor Genes:

Human cells become malignant through the activation of oncogenes and inactivation of tumor suppressor genes. The pattern of genes involved varies markedly at different organ sites. Oncogenes stimulate cell proliferation and may be overexpressed by gene amplification (e.g. MYC). In addition, oncogenes may be activated by mutations (e.g. the RAS gene family). Tumor suppressor genes are typically inactivated by gene mutations in one allele (gene copy), followed by the loss of the intact allele during cell replication (two-hit mechanism). This leads to loss of expression and abolition of the suppressor function, which is particularly important in cell cycle control. Mutational inactivation of suppressor genes in germ cells is the underlying cause of most inherited tumor syndromes. The same type of mutation may arise through mutations occurring during an individual’s lifetime.

American Type Tissue Collection: http://www.atcc.org
Centers for Disease Control and Prevention, Atlanta: http://www.cdc.gov
Cancer Genome Anatomy Project: http://www.ncbi.nim.nih.gov/ncicgap/
European Bioinformatics Institute: http://www.ebi.ac.uk/
Kyoto Encyclopedia of Genes and Genomes: http://genome.ad.jp/kegg/kegg.html
Protein Data Bank (a protein structure database): http://www.rcsb.org/pdb/

The Cell Cycle:

The control of cell division is critical to normal tissue structure and function. It is regulated by a complex interplay of many genes that control the cell cycle, with DNA replication (S phase) and mitosis as major checkpoints. The cell cycle is tightly regulated to minimize transmission of genetic damage to subsequent cell generations. Progression through the cell cycle is primarily controlled by cyclins, associated kinases, and their inhibitors. Retinoblastoma (RB) and p53 are major suppressor genes involved in the G1/S checkpoint control. Cancer may be perceived as the consequence of loss of cell cycle control and progressive genetic instability.

Animation of the phases of the cell cycle and of mitosis: http://www.cellsalive.com/
Nature Reviews, “Focus on cell division”: http://www.nature.com/ncb/celldivision/
Forsburg Lab, guide to the cell cycle and DNA replication in S. pombe: http://pingu.salk.edu/~forsburg/lab.html

Cell-Cell Communication:

Cells communicate by means of secreted molecules which affect neighboring cells carrying appropriate receptors, and also by direct cell contact, including specific gap junctions. Cell contact-mediated communications through gap junctions is controlled by connexin genes and is often disrupted in cancer. This may contribute to uncontrolled and autonomous growth. Interventions restoring gap junction communications may provide a basis for therapy.

Apoptosis

The term apoptosis refers to a type of cell death that occurs both physiologically and in response to external stimuli, including x-rays and anticancer drugs. Apoptotic cell death is characterized by distinctive morphological changes different from those occurring during necrosis, which follows ischaemic injury or toxic damage. Apoptosis is regulated by several distinct signaling pathways. Dysregulation of apoptosis may result in disordered cell growth and thereby contribute to carcinogenesis. Selective induction of apoptosis in tumor cells is among current strategies for the development of novel cancer therapies.

The European Cell Death Organaization: http://www.ecdo.dote.hu/

Invasion and Metastasis

The ability of tumor cells to invade and colonize distant sites is a major feature distinguishing benign growths from malignant cancer. Most human cancers lead to death through widespread metastasis rather than the adverse local effects of the primary neoplasm. Often, metastatic spread first involves regional lymph nodes, followed by hematogenous spread throughout the body. Metastases may become clinically manifest several years after surgical resection of the primary tumor. Current methods are inadequate for the routine detection of micrometastases and the search for effective, selective therapies directed toward metastatic growth remains a major challenge.

The Metastasis Research Society (UK): http://www.metastasis.icr.ac.uk