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Cell division (or proliferation) is a highly regulated process in normal cells.

A hallmark of cancer cells and tumors, however, is uncontrolled proliferation. In these quickly dividing cancer cells, pathways that are only supposed to be turned on temporarily for specific functions are often activated in an uncontrollable manner. Curcumin, a pigment derived from the plant turmeric, has been shown to reduce cell division and increase cell death (apoptosis) through inhibition of inflammation pathways in many different cancer cell types (for a full review, see the reference below). However, the effects of curcumin on cellular processes in esophageal cancer cells have not been studied extensively to date. In a recent article in PLoS One, Subramaniam and colleagues identified modulation of Notch signaling as a new mechanism by which curcumin influences proliferation and apoptosis in esophageal cancer cells. The authors found that spheroid formation, a method of growing clusters of cells three-dimensionally to study tumor formation in culture, was inhibited when esophageal cancer cells were treated with curcumin. Because self-renewal is required for spheroid formation, and Notch is one signaling pathway that is involved in maintaining self-renewal and driving cell division, the authors investigated effects of curcumin treatment on Notch signaling.

The Notch pathway, when activated, sends a signal to the cell nucleus, where DNA is housed, to drive expression of certain genes that influence many cellular processes required for normal cell growth and maintenance. Notch signaling is upregulated in esophageal cancers, causing misregulation of these critical processes. Subramaniam et al found that levels of Notch-1, the protein that starts the signaling cascade, and levels of downstream target genes of Notch-1, were reduced when esophageal cancer cells were treated with curcumin. Curcumin treatment also reduced levels of the proteins that form a complex with γ(gamma)-secretase; this group of proteins is required to send the Notch signal to the nucleus.

Interestingly, the authors found that when cells were treated with curcumin and DAPT, an inhibitor of γ-secretase, this combination enhanced the effect of curcumin alone: cell death increased even more, while cell division was further decreased. The findings in the present study contribute to the growing understanding of the mechanisms by which curcumin provides anti-tumorigenic effects in esophageal cancer cell lines.

While there is hope that curcumin may provide therapeutic effects in cancer patients, many more clinical studies are needed to determine if this is indeed the case. Phase II trials using curcumin in esophageal cancer patients thus far are lacking and phase II trials investigating the effects of curcumin on tumors in other organs such as colon and pancreas have provided mixed results. Curcumin is well tolerated by patients and does not appear to produce negative side effects. While some patients seem to not respond to curcumin treatments, others respond well and show reduction in tumor growth, and therefore these studies remain inconclusive (reviewed in [1]). Because studies testing the effects of curcumin on esophageal cancer cells have been done in culture dishes, future studies will need to address whether or not curcumin exhibits similar anti-tumorigenic results in animal models, and more importantly, in esophageal cancer patients.

Original Article: here

Curcumin Review: here

In a phase 2 study performed on patients with advanced esophageal cancer, Hiura et al. showed that supplementation with exogenous ghrelin during cisplatin-based chemotherapy promotes appetite and improves food intake.

Cisplatin is a widely used chemotherapy drug that acts by crosslinking DNA, thereby causing cells to arrest during cell division, activate cell cycle checkpoints, and eventually undergo programmed cell death. Quickly dividing cancer cells are efficiently killed during cisplatin treatment. However, side effects from chemotherapy are harsh and can lower quality of life significantly, and sometimes even cause patients to terminate chemotherapy treatment. Included in the many side effects are anorexia and nausea, which cause a decrease in caloric intake and are worst in the week following chemotherapy treatment. Even when patients take 5HT antagonists with the initial chemotherapy treatment to help reduce nausea, side effects persist and remain problematic. Therefore, scientists have been investigating other methods to prevent these negative effects.

In a study recently published in Cancer (go here to read the full article), Hiura and colleagues tested whether ghrelin supplementation during chemotherapy would help improve nausea in 40 patients (20 test subjects, 20 placebo control subjects) in the week following treatment. Ghrelin, a growth hormone receptor ligand that is secreted by gastric endocrine cells, is a positive signal for appetite and food intake. Studies in rodents have shown that cisplatin treatment reduces ghrelin levels. In patients who have undergone gastrostomy and esophagectomy, administering ghrelin exogenously increases oral feeding and decreases weight loss. The authors therefore administered ghrelin, or saline as a placebo control, to advanced stage esophageal patients receiving cisplatin as part of chemotherapy treatment to test whether ghrelin would increase appetite in these patients. Blood tests revealed that while patients showed no signs of changes in hormone levels, the placebo group had lower overall levels of proteins that serve as nutritional markers. Surveys completed by the patients showed that those in the ghrelin group reported reduced adverse affects of nausea and anorexia as compared to the placebo control patients. Ghrelin administration also appeared to reduce the length of stay in the hospital following chemo treatment, but this result was not significant. Importantly, the authors found no difference in the tumor response rate for the ghrelin group as compared to the placebo control group. Overall, the authors concluded that exogenous administration of ghrelin may improve quality of life, increase caloric intake, and reduce nausea in the week following chemotherapy. If the results hold in broader studies: over longer time periods, using many more patients, supplementation with ghrelin could provide one exciting new mechanism to help patients sustain chemotherapy and be more comfortable during treatments.

Lower levels of OCT4 in esophageal cancer tissue correlated positively with longer survival in Chinese patients.

OCT4 is a transcription factor, a kind of protein that binds to certain regions of DNA to turn on genes. This transcription factor is expressed in embryonic stem cells and is important for maintaining their pluripotency, or ability to differentiate into cells of any of the three germ layers, and ability to self-renew. Tumor cells often display properties similar to stem cells; they are invasive and can divide continuously. Because of the similarities between stem cells and some tumor cells, it is hypothesized that factors required for embryonic stem cell growth, such as OCT4, are turned on again in tumor cells to maintain the invasiveness and immortality characteristic of this de-differentiated state. In support of this idea, OCT4 is expressed at extremely low levels in normal somatic cells but is upregulated in many types of human tumors.

So what is the relationship between OCT4 and esophageal cancer? In a study recently published in World Journal of Gastroenterology, He, Fan and colleagues found that lower levels of OCT4 in esophageal cancer tissue correlates positively with longer patient survival. Using PCR (to detect OCT4 at a DNA level) and Western blotting (to detect OCT4 at the protein level) the authors first showed that OCT4 is expressed in multiple esophageal cancer cell lines. The authors then obtained tumor samples from 153 Chinese patients, stained the samples to detect OCT4 protein, and categorized the patients into groups expressing either low, moderate, or high levels of OCT4. Tumors from 27 patients had high OCT4 expression levels, and after about 150 months, only 20% of these patients survived, compared to 50% of patients with tumors expressing low levels of OCT4. This represents a 2.6-fold increase in tumor-related death. Interestingly, the authors also found that high OCT4 levels correlated to higher histological grade in tumors, indicating greater de-differentiation and less similarity to normal esophageal tissue, but no correlation between OCT4 expression and age, gender, tumor size, or clinical stage.

Esophageal cancers are often resistant to chemotherapy, and therefore esophageal cancer patients have poor prognosis. While chemotherapy usually kills the mass of the tumor cells, it is proposed to be ineffective against a stem-cell like population of tumor cells, which can lead to reoccurrence and metastasis. Knowing OCT4 is expressed at high levels in tumors and correlates with poor prognosis is the foundation for future studies investigating the specific role of OCT4 in tumor cells, which could potentially lead to therapies that will target OCT4 and similar cancer-specific molecules.

Pitt Study: Esophageal Cancer Risk Higher in Medically Treated GERD Patients with Fewest Symptoms

University of Pittsburgh researchers have found that patients with lower levels of GERD symptoms have an increased likelihood of developing esophageal cancer. Patients with mild symptoms of GERD are less likely to be screened for Barrett's esophagus - a common precursor to cancer - than those with more severe symptoms. Read a complete analysis of the research here.

Scientists use stem cell-cancer cell hybrids to decrease tumor progression

In a study recently published in the International Journal of Oncology, scientists at the Chinese Academy of Sciences in Beijing showed that fusing human umbilical stem cells (human mesenchymal stem cells, or hMSC) with esophageal cancer cells (ECC), reduces the tumor-forming potential of the hybrids when compared to esophageal cancer cells alone. The researchers, led by Yong Wang in the lab of Shixin Lu, studied the tumorigenicity of these hybrids in cell culture and in mice. A hallmark of cancer cells is their increased rate of growth and division, as well as their resistance to apoptosis - the process of programmed, intentional cell death.

Apoptosis is a critical process by which old, defective or mutated cells self-destruct in order to allow turnover of normal tissues (in the case of old cells) or to prevent propagation of defects (in the case of genetic mutations). Remarkably, fusion of the hMSCs with ECCs led to increased apoptosis. In mice, tumors containing hybrid cells were significantly smaller, and had a longer latency period.

Furthermore, Wang and colleagues showed that a protein called DUSP6, shown in the past to be expressed at lower levels in ECCs, significantly increased apoptosis and inhibited growth when added back to those cells in culture. Researchers have a long way to go before developing methods such as the hybridization described by Wang et al into therapies, but work such as this helps scientists understand the processes and signals that could lead to improved treatments and outcomes for esophageal cancer.

Further Reading

Common mutation in skin and lung squamous cell carcinomas identified

Protein receptors that take signals from outside of a cell and activate cellular responses (e.g. telling the cell to grow, divide, or produce anti-inflammatory molecules) are critical to normal development of tissue, as well as maintaining homeostasis in fully developed tissues. The Notch receptors are proteins embedded in cell membranes that receive signals from nearby cells. Notch signaling is important in helping cells to decide how to develop as they grow from early-stage "progenitors" into more functionally specific daughter cells. In squamous cell carcinomas (SCC), this differentiation process is defective, leading to abnormal daughter cells that ultimately form tumors. SCCs can affect the esophagus, lungs, skin, and cervix.

In a recently published study in the Proceedings of the National Academy of Science, an interdisciplinary group of scientists led by Nicholas Wang and Zachary Sanborn of Lawrence Berkeley National Laboratory, and Raymond Cho of the University of California, San Francisco, identified several previously unknown mutations in the Notch family of receptors in skin and lung tumors which lead to defective Notch signaling. Their results indicate "that [non-functional] Notch plays a prominent role in multiple variants of SCC." Previous work from other studies showed that mutations causing hyperactive Notch play a role in cancers such as leukemia. As a result, cancer researchers have looked into the possibility of inhibiting Notch activity as a way of treating leukemia. However, this work by Wang et al, along with previous research showing reductions in Notch activity in skin cancers, is important for indicating that the context/location of Notch activity is critical for understanding its effects on cancer formation. Furthermore, these studies confirm that cancer therapies designed to inhibit Notch signaling have to take into account the potential side effects (some of which have been observed) of blocking this pathway.

Further Reading

National Cancer Institute awards multi-site, $8 million grant to study Barrett's Esophagus.

The grant will fund research to help develop models of Barrett's esophagus and its progression to esophageal adenocarcinoma, and includes researchers from Penn State, Columbia University, and the Mayo Clinic. Additionally, the group funded by this grant will coordinate efforts with researchers at the University of Michigan and Vanderbilt University.

For more, see the Penn State press release.

Analysis of 500,000 adults reveals no association between fat intake and esophageal cancer.

Healthy diet and lifestyle are keys to reducing the risk of cancer. However, a statistical analysis of nearly 500,000 adults recently published in the International Journal of Cancer indicates that increased dietary fat intake is not associated with increased risk for esophageal cancer, as has been previously suggested by some (but not all) studies.

In the report, researchers looked at approximately half a million adults ages 50-71 who, in 1995-96 filled out health surveys provided by the AARP. These surveys included questions on diet and health activities. Using state cancer registry databases, the researchers were able to determine who in the original group had been diagnosed with various forms of esophageal and gastric cancers. Statistical analysis controlling for other variables including but not limited to age, gender, smoking habits, and ethnicity, showed that although survey respondents who reported higher fat intake were more likely to contract diabetes, the same was not true for esophageal cancer.

Breaking down the results by fat type and source of the fat (i.e. red meat vs. margarine), the researchers still saw no significant correlation between fat intake and esophageal cancer. This study was one of the few to look at the potential association between fat intake and esophageal cancer, and among those was the largest, leading to much stronger statistical confidence in the results.

As with any study, the authors note limitations to their methodology, and, these results do not nullify the need for healthy diet and lifestyle in disease prevention. However, the work done in this analysis provides a valuable clarification of previously inconsistent results.

Further Reading