Environmental Cues Lead to Breast Cancer
A group led by Dr. Peter Lloyd Jones at the University of Dundee, Dundee, Scotland; the University of Colorado Denver, Aurora, CO; and the University of Pennsylvania, Philadelphia, PA has demonstrated that tenascin-C affects proto-oncogene function in breast cancer. Their report can be found in the February 2010 issue of The American Journal of Pathology.
Breast cancer causes over half a million deaths annually worldwide. Much research has focused on the role of cancer-causing oncogenes and their precursors, non-carcinogenic proto-oncogenes, within the breast epithelium, the tissue from which most breast cancers are derived. The role of the surrounding cells, or stroma, and the molecules they secrete, such as the extracellular matrix, on transformation of proto-oncogenes to oncogenes in breast cancer remains relatively unexplored.
To determine how stromal extracellular matrix remodeling affects proto-oncogene expression in breast epithelia, Taraseviciute et al developed a computational model to quantify changes in a 3-D culture of human mammary epithelial cells. They found that tenascin-C, a stromal glycoprotein whose expression correlates with disease severity, promoted cancer-like properties, similar to the results of overexpression of the oncogene c-met. Indeed, tenascin-C increased c-met expression, and tenascin-C-induced carcinogenesis was inhibited by blocking c-met function. Taken together, these results indicate
a role for stromal changes in regulating proto-oncogene function.
Dr. Jones and colleagues suggest "that micro-environmental cues originating within the tumor stroma can act in both a dominant and paracrine fashion to control the expression and function of epithelial genes already associated with the development and progression of breast cancer."
Taraseviciute A, Vincent BT, Schedin P, Jones PL: Quantitative analysis of 3-D human mammary epithelial tissue architecture reveals a role for tenascin-C in regulating c-met function. Am J Pathol 2010, 176: 827-838
Wnt Signaling Key in Rare Skin Disease
Dr. Kenji Kabashima and colleagues at the Kyoto University Graduate School of Medicine have discovered that Wnt signaling is involved in the development of pachydermoperiostosis. They present these findings in the February 2010 issue of The American Journal of Pathology.
Pachydermoperiostosis is a rare skin disease characterized by pachydermia (skin thickening), digital clubbing, and periostosis (abnormal bone deposits) of long bones. Fibroblasts help to form the structural framework for various tissues, including the skin and bones, and therefore likely play a role in this process.
As the Wnt signaling pathway plays a developmental role in both bone and skin, Kabashima et al hypothesized that Wnt signaling was involved in the development of pachydermia. They found that DKK1, a Wnt-signaling antagonist, was expressed at lower levels in pachydermoperiostosis than in control fibroblasts, whereas the Wnt-signaling molecule β-catenin was expressed at higher levels. In addition, expression of DKK1 inhibited fibroblast proliferation, and DKK1-inhibition increased skin thickening in mouse ears. Therefore, enhanced Wnt signaling may contribute to pachydermia by increasing levels of fibroblast proliferation.
Dr. Kabashima and colleagues therefore conclude that "enhanced Wnt signaling is related to the development of pachydermia."
Kabashima K, Sakabe J-i, Yoshiki R, Tabata Y, Kohno K, Tokura Y: Involvement of Wnt signaling in dermal fibroblasts. Am J Pathol 2010, 176: 721-732
Chronic Morphine Use Delays Wound Healing
Researchers led by Dr. Sabita Roy at the University of Minnesota have found that chronic morphine use delays wound healing in the presence on an infection. They report their data in the February 2010 issue of The American Journal of Pathology.
Morphine acts on cells in the central nervous system, resulting in pain relief and analgesia; however, morphine use may also affect the immune system. Indeed, chronic morphine users and opioid abusers have inadequate wound closure and increased susceptibility to infection.
To further address this issue, Martin et al examined wound healing in a mouse model of chronic morphine use/abuse. In the presence of inflammation, chronic morphine exposure resulted in a marked decrease in wound closure, compromised wound integrity, and increased bacterial sepsis. With morphine exposure, expression of particular immune molecules was altered, which led to decreased recruitment of immune cells to the wound site. New blood vessel formation and recruitment of replacement cells were also suppressed in these animals. These data suggest that the immunosuppression due to morphine treatment delays immune cell recruitment, leading to lack of bacterial clearance and delayed wound closure.
Dr. Roy's group concludes that "these studies provide an in vivo tool by which further mechanistic experiments can be performed to address why, clinically, heroin-addicted patients often present with infected non-healing wounds. Understanding these underlying mechanisms affords improved treatment options not only for chronic morphine users and abusers, but can also have translational implications for immuno-compromised populations such as the elderly or those who are chronically stressed."
Martin JL, Koodie L, Krishnan AG, Charboneau R, Barke RA, Roy S: Chronic Morphine Administration Delays Wound Healing by Inhibiting Immune Cell Recruitment to the Wound Site. Am J Pathol 2010, 176: 786-799
Diabetic Toxicity
A group led by Dr. Peter C. Butler of the University of California, Los Angeles, CA has discovered that small clusters (oligomers) of islet amyloid polypeptides (IAPPs) may contribute to the onset of type 2 diabetes mellitus. These results are presented in the February 2010 issue of The American Journal of Pathology.
Type 2 diabetes, or non-insulin-dependent diabetes, is characterized by high blood glucose in the presence of insulin resistance. Rates of diabetes doubled in the United States between 1990 and 2005, with nearly 23.6 million people diagnosed with diabetes.