Environmental Factor, May 2010, National Institute of Environmental Health Sciences
Ground-breaking Research Leads to New Cancer Theory
By Brian Chorley, Ph.D.
Cancer researchers tackle the nearly insurmountable task of identifying the mechanisms of carcinogenesis - the processes of transforming normal cells into cancer cells.
Two such theorists are NIEHS grantees working at Tufts University School of Medicine in Boston. Carlos Sonnenschein, M.D., and Ana Soto, M.D., have dedicated the majority of their research careers to describing the signals that mediate cellular proliferation. On April 20, the researchers presented their findings during a seminar at NIEHS on investigations of chemicals that mimic the biological actions of estrogen. Their talk, "Carcinogenesis: Development Gone Awry," also presented evidence from their experiments that lend support to a new theory of carcinogenesis.
The current scientific consensus is that cancer-causing agents result in the uncontrolled proliferation of a single cell. Because this paradigm cannot explain all tumors, Soto and Sonnenschein have developed an alternative theory to describe these not-so-uncommon exceptions.
The tissue organization field theory of carcinogenesis
The prevailing sporadic carcinogenesis theory, known as the somatic mutation theory, explains that carcinogens mutate cells that are normally in a non-growing, quiescent state. These mutations lead to a cascade of programmatic errors that cause a state of irreversible proliferation. Therefore a change in a single cell can lead to tumor formation.
Sonnenschein, drawing on the connection between carcinogenesis and tissue development, explained why this scenario may not always be the case. "Development is not a program," he said. "Development decisions are made instead by an ad hoc committee."
In his tissue organization field theory of carcinogenesis, Sonnenschein characterizes cancer as a disease of the tissue organ. Cells, he explained, are in a default state of proliferation and motility - constantly maintaining homeostasis of the tissue through cellular communication and organization. Disruption of this organization can lead to disease states, such as cancer, as carcinogens target whole tissues, not just individual cells.
Sonnenschein's theory may account for some situations that somatic mutation theory fails to explain. For example, some cancers are not autonomous - that is, the cancerous cells do not control their own fate. Uncontrolled cellular proliferation, therefore, may be signals from the surrounding milieu, not just simply errors in the cell's replication machinery.
Bisphenol A alters mammary tissue organization
To support this theory, Soto focused on the team's mammary development studies in rodents exposed to the xenoestrogen, bisphenol A (BPA).
Pre-natal exposure to BPA, a common component of plastics, alters normal mammary gland development in these models. Soto's findings demonstrated that in mice BPA accelerates mammary maturation by increasing epithelial cell branching, reorganizing connective tissue, and altering fat deposits. In rats, a common animal model for breast cancer, BPA caused pre-cancerous lesions in the mammary tissue.
These lesions were directly linked to tissue disorganization caused by the BPA exposure during gestation and lactation.
The mechanisms are still unclear
While altered mammary development due to BPA exposure led to abnormal cellular proliferation in these rodent models, the cellular signaling mechanisms involved are still being teased out.
Soto described multiple experiments in progress. One exciting finding was that the methylome - the methylation patterns of the genome - changed constantly with BPA exposure. Soto explained that thousands of methylation sites were altered, but these changes were inconsistent over different points of time during and after the BPA exposure. The challenge is to determine if these methylation changes are causative or simply consequences of the tissue disorganization.
Parallel gene expression analysis may solve part of the mechanistic mystery. Soto believes the preliminary results are encouraging. "The molecular results are consistent with the [mammary] histology... the locale and time of [BPA] exposure is of the essence," she explained.
NIEHS Cellular, Organs, and Systems Pathobiology Branch Acting Chief Jerry Heindel, Ph.D., oversees NIEHS grants supporting the research by Soto and Sonnenschein on the developmental toxicity of BPA(http://tools.niehs.nih.gov/portfolio/sc/detail.cfm?appl_id=7660435) and mammogenesis and neoplasia(http://tools.niehs.nih.gov/portfolio/sc/detail.cfm?appl_id=7857542). Heindel was host for the talk, which was sponsored by NIEHS/NTP Director Linda Birnbaum, Ph.D.