Laboratory of Molecular Carcinogenesis

Research Summary

Carcinogenesis is a complex process. In any individual, the interplay between genetics, environmental exposure and age combine to create conditions more or less favorable for the development and dissemination of cancer. For cancer cells to develop and thrive, they must acquire a variety of specific capabilities: growing inappropriately, avoiding elimination by defense mechanisms, stimulating their microenvironment, providing needed support and spreading to new locations within the body. The processes that regulate these acquired abilities include gene expression as controlled by chromatin structure, signal transduction events in response to cell-cell interactions, hormone exposure and fatty acid metabolism and DNA damage and repair responses. The Laboratory of Molecular Carcinogenesis (LMC) — headed by Laboratory Chief Trevor K. Archer, Ph.D. (http://www.niehs.nih.gov/research/atniehs/labs/lmc/resources.cfm#message) — is dedicated to elucidating the molecular mechanisms that facilitate these processes in the hope that understanding will lead to improved cancer prevention and therapy.

The goal of the LMC is to define the fundamental molecular mechanisms by which environmental exposures lead to cancer. The pursuit of molecular and environmental causes of cancer represents a synergistic approach to cancer prevention and treatment. Knowing the target genes for environmental agents will permit the development of improved methods for the identification of environmental carcinogens in both laboratory and epidemiological studies.

Bioluminescent Images of Tumor-bearing Mice
Human breast carcinoma cells expressing firefly luciferase were injected into the mammary fat pads of nude (immunocompromised) female mice. To visualize the location of tumor cells, mice were injected intraperitoneally with luciferin, then anesthetized and placed in the Caliper Spectrum in vivo imaging system at NIEHS. Each image shows an overlay of the bioluminescent signal on a white light image of the mouse (ventral view).
A) Mouse showing bioluminescent signal from the primary tumor in the mammary fat pad 6 weeks after injection of tumor cells. Note the scale indicates the most intense pixels represent approximately 1 x 109 photons/sec/cm2.
B) Same mouse, imaged one week after surgical resection of the primary tumor, showing three areas of bioluminescence: 1) potential remaining cells from primary tumor, or metastasis to adjacent fat pad; 2) potential metastasis to another mammary fat pad or axillary lymph nodes; and 3) potential lung metastasis. Maximal bioluminescent signal in this mouse was approximately 1 x 104 photons/sec/cm2 which would not have been visible when the primary tumor was present.
C) Another mouse imaged one week after the primary tumor was surgically resected. Note the absence of tumor over the mammary fat pad, but the appearance of bioluminescence over the chest. The most intense signal from this apparent lung metastasis represents approximately 4 x 104 photons/sec/cm2. (D. Ray and J. Roberts)

The LMC is comprised of eight independent research groups forming a multidisciplinary team of cancer researchers with expertise in biochemistry, cell biology, epidemiology, molecular biology and oncology. LMC scientists bring diverse perspectives to their work, which provides an ideal opportunity for the study of cancer from the molecular level to the clinical. The LMC is actively involved in the following basic research:

• Impact of chromatin and epigenetics on gene transcription
• Signal transduction events in response to cell-cell interactions
• Hormone exposure and fatty acid metabolism
• DNA damage and repair responses
• Molecular characterization of stem cell models
• Mechanisms of action of specific genes in cell signaling, cell proliferation and cell death

Environmental agents influence cancer development by causing mutation in critical target genes, epigenetic modifications and by altering signal transduction pathways in and between cells, all active areas of research in LMC.

Strong ties with the Environmental Toxicological Program (ETP) and the Epidemiology Branch of the NIEHS allows LMC to be very active in the understanding of the etiology of cancer. The LMC is dedicated to elucidating the molecular mechanisms that facilitate these processes in the hope that understanding will lead to improved cancer prevention and therapy.

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