Recent Publications by VICC Researchers

November 21, 2013

Vanderbilt-Ingram Cancer Center is committed to conducting innovative and high-impact basic, translational and clinical research with the greatest potential for making a difference for cancer patients, today and in the future. Here’s a sampling of work published in peer-reviewed journals by Cancer Center investigators in 2012-2013:

 

Study identifies new mechanism for cancer development

Bhuminder Singh, Ph.D., and Robert Coffey, M.D., discovered a new mechanism for the development of cancer that is challenging conventional scientific wisdom. They describe how “mistrafficking” of a ligand, a protein that binds to the EGF receptor, can “transform” epithelial cells into a particularly vicious tumor in mice. The report, published in the May 28 issue of Proceedings of the National Academy of Sciences, is the first to demonstrate transformation of polarized epithelial cells by mistrafficking of an EGF receptor ligand called epiregulin to the cell’s outer, “apical” surface. Conventional wisdom has held that these receptors don’t serve any important function, but the research showed that when, in a mouse model, epiregulin bound with the small number of EGF receptors there, it triggered massive transformation—cancer.

 

Overcoming resistance in ovarian cancer

To identify possible roles for the nuclear receptor TR3 in ovarian cancer, Dineo Khabele, M.D., and colleagues studied TR3 expression in a tissue microarray generated from ovarian tumor samples. The investigators found that low TR3 expression was associated with resistance to platinum chemotherapy and poorer overall survival. In cultured ovarian cancer cells, they showed that TR3 moved from the nucleus to the cytoplasm in cells that were sensitive to cisplatin, but not in resistant cells. Experimentally lowering the expression of TR3 reduced the effects of cisplatin on apoptosis and cell growth. The findings, reported Aug. 1 in Cancer Research, suggest that disruption of TR3 activity contributes to platinum chemotherapy resistance in ovarian cancer. Increasing TR3 function may be a therapeutic strategy for overcoming this resistance.

 

Study helps define pancreatic cancer’s cellular origins

Christopher Wright, D.Phil., and colleagues at the University of California, participating in the Beta Cell Biology Consortium, have now discovered the “cell of origin” for pancreatic ductal adenocarcinoma, the most common form of pancreatic cancer. They report in the November 2012 issue of Cancer Cell that digestive enzyme-secreting cells of the pancreas (acinar cells)—not ductal epithelial cells as previously believed—give rise to pancreatic tumors. The findings will make it possible to explore the earliest changes that give rise to pancreatic cancer. The studies also introduce a mouse model with focal, adult-stage pancreatic cancer that is the best current mimic of human pancreatic adenocarcinoma.

 

Factor’s yin-yang tumor effects

Tumor necrosis factor-alpha (TNF-alpha) is produced by most malignant cells, but its role in cancer progression—pro- or anti-tumor—is conflicting. Pampee Young, M.D., Ph.D., and colleagues including Pierre Massion, M.D., explored whether the two different forms of TNF-alpha—membrane-bound (mTNF-alpha) and soluble (sTNF-alpha)—have distinct actions that contribute to the varying findings. Using mouse lung and melanoma tumor cell lines, they demonstrated that sTNF-alpha promotes cancer growth and mTNF-alpha inhibits tumor growth by reducing the number of tumor-associated myeloid cells. They also found that human non-small cell lung cancer tissues have differing expression of membrane versus soluble TNF-alpha, and that patients whose tumors had gene “signatures” consistent with higher levels of mTNF-alpha had improved survival compared to tumors with more sTNF-alpha. The findings, reported in the July 1 issue of Cancer Research, suggest that the two forms of TNF-alpha have opposing effects on tumor progression—an insight that is critical for the effective use of TNF-alpha inhibitors, which can block both forms.

 

Tumor factor spurs blood vessel growth

Graduate student Nicole Al-Greene, R. Daniel Beauchamp, M.D., and colleagues have identified a new regulator of tumor angiogenesis in colorectal cancer. They found increased levels of “four jointed box 1” (FJX1) mRNA and protein in human colorectal tumor epithelium compared to normal and adenoma epithelial tissue. High expression of FJX1 was associated with poor patient prognosis and was correlated with changes in known angiogenesis genes. The investigators demonstrated that increased FJX1 expression in colon cancer cells promoted tumor growth and vascularization in a mouse model. In vitro, the culture media from FJX1-expressing cells promoted endothelial capillary tube formation. The results, reported in July in PLOS ONE, support the conclusion that FJX1 regulates colorectal tumor progression through effects on angiogenesis and suggest that FJX1 may be a valuable target for new cancer therapies.

 

Predicting cancer’s response to therapy

Neoadjuvant chemotherapy (NAC) is increasingly used in women with locally advanced breast cancer before surgical treatment. Early assessment of response to NAC would allow clinicians to identify patients who are not responding and adjust their therapy. Thomas Yankeelov, Ph.D., and colleagues obtained two types of magnetic resonance imaging—diffusion-weighted and dynamic contrast-enhanced—for 28 patients before treatment, after one cycle, and after completion of all cycles of NAC. They used the imaging data in a logistic model of tumor growth to calculate a proliferation rate after one cycle and from that, to predict the tumor cell number after NAC completion. They report in the June issue of Translational Oncology that the proliferation rate after one cycle was able to separate patients who went on to achieve a complete response (assessed after surgery) from those who did not. The methods, if validated in more patients, could be used to predict patient outcome early in the course of NAC.

 


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