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‘Breast on a chip’: testing nanomedical methods for cancer detection and treatment

Researchers from Purdue University have created a model for breast cancer research that is the size of a slide. It will be used to assess nanomedical approaches for the detection and treatment of breast cancer.

The majority of breast tumors originate in the mammary duct system. The new model mimics this system and can be used to study the use of nanoparticles to seek and target tumor cells. The eventual goal is to introduce magnetic nanoparticles to the mammary ducts through openings in the nipple and then guide these particles with a magnetic field through the ducts, where they would attach to cancer cells.

“Nanoparticles can be designed to latch on to cancer cells and illuminate them, decreasing the size of a tumor that can be detected through mammography from 5 mm to 2 mm, which translates into finding the cancer ten-times earlier in its evolution”, anticipated James Leary, who led the team with Lelièvre and is SVM Professor of Nanomedicine and professor of basic medical sciences in the School of Veterinary Medicine, and professor of biomedical engineering in the Weldon School of Biomedical Engineering. “There also is great potential for nanoparticles to deliver anticancer agents directly to the cancer cells”.

The team developed a model to house cells that line the ducts of the mammary system. On this model, Leary created a mold of branching channels out of polydimethylsiloxane, a rubber-like material. The channels were just 5 mm long and range from 20 to 100 μm in diameter, the size of a human hair.

Lelièvre's group complimented the model by growing the complex cells that line the mammary ducts and adding them to the model duct, encouraging them to grow and behave as normal human breast cells.

“The cells within the breast ductal system have a very specific organization that has proven difficult to obtain in a laboratory”, explained Lelièvre. “The cells have different sides, and one side must face the wall of the duct and the other must face the inner channel. Reproducing this behavior is very challenging, and it had never been achieved on an artificial structure before”.

To date, the researchers have demonstrated that nanoparticles can be moved within the mold filled with fluid, but have not yet moved the particles through the final model, which includes the lining of living cells. The creation of this model is an important milestone in their work and, according to Lelièvre, is “a testament to what can be accomplished through multidisciplinary research”.

Sources: Grafton MMG, Wang L, Vidi P-A, Leary J, Lelièvre SA: Breast on-a-chip: mimicry of the channeling system of the breast for development of theranostics. Integr. Biol. doi: 10.1039/C0IB00132E (2011) (Epub ahead of print); Purdue University: www.purdue.edu/newsroom

Genetic signature helps pinpoint the culprits of breast cancer drug resistance

A study by researchers at the Biodesign Institute at Arizona State University, USA, has identified over 30 breast cancer gene targets that contribute to resistance to leading chemotherapy treatment.

Tumor resistance to antihormone therapy in breast cancer remains a serious therapeutic problem that has eluded vigorous attempts to understand the critical pathways that contribute to it. The results of this new study may provide a new tool to identify patients who may become resistant to chemotherapy.

Led by Dr Josh LaBaer, Virginia G Piper Chair in Personalized Medicine at Arizona State University (ASU) and director of the Center for Personalized Diagnostics at the Biodesign Institute, researchers employed an unbiased and systematic approach using subcloned breast cancer cell lines that were either very sensitive (>90% death) or naturally resistant (proliferate in the presence of drug) to the antihormone tamoxifen. By comparing the gene expression patterns in the sensitive and resistant cells in response to tamoxifen, genes whose response to tamoxifen was altered in the resistant cells were identified. In women with breast cancer, tumors that had this ‘drug resistance’ signature relapsed earlier for women taking tamoxifen in two different clinical studies.

In addition, the laboratory's extensive collection of fully sequenced human genes were used to test more than 500 human kinases to establish if any of them could make the sensitive cells become resistant. Subsequently, over 30 kinases that repeatedly allowed the sensitive cells to grow in the presence of the drug were identified. Commenting on this finding, Dr LaBaer remarked: “This provided us with clues about the genes which might contribute to drug resistance in women”.

Interestingly, both of the approaches led the researchers to an atypical kinase, HSPB8, which appears to make cells resistant by the surprising mechanism of blocking autophagy, a process in which cells consume their own proteins in order to survive in low-nutrient conditions.

When asked how to move forward from the results of the study, Dr LaBaer answered: “From the kinases identified in our study several were already known, but many are novel and could be exploited in the future as potential drug targets”.

Source: Gonzalez-Malerva L, Park J, Zou L et al.: High-throughput ectopic expression screen for tamoxifen resistance identifies an atypical kinase that blocks autophagy. Proc. Natl Acad. Sci. USA 108(5), 2058–2063 (2011).

Antidepressants could reduce hot flashes in menopause

Researchers at the University of Pennsylvania School of Medicine, PA, USA, have revealed that the frequency and severity of hot flashes could be reduced in women who are in either the transition to menopause or were postmenopausal, by administration of the antidepressant escitalopram.

Hot flashes are a symptom of menopause, but do not affect all women. They are characterized by a spreading feeling of warmth, which can be anywhere on the body, but is often concentrated in the head and neck. Flashes are a symptom of the changing hormone levels that occur during menopause.

Scientists evaluated the efficacy of escitalopram versus a placebo to reduce the frequency and severity of hot flashes in healthy women. The important modifiers of race, menopausal status, depressed mood and anxiety were also examined.

The randomized trial was a multicenter study including 205 women, and a number of racial groups were evaluated. The women were prescribed 10–20 mg per day of escitalopram, or a matching placebo, for a period of 8 weeks. The frequency and severity of the flashes was assessed by prospective daily diaries at weeks 4 and 8.

The study indicated that escitalopram was associated with a significant reduction in the frequency of hot flashes in comparison with the placebo. The results were adjusted for race, site of heat and baseline frequency of hot flashes. The hot flash frequency at week 8 was found to have reduced by 47% for those women receiving escitalopram, whereas the group receiving the placebo experienced a 33% reduction.

Although the decrease in hot flash frequency and severity may appear modest, the participants of the study indicated that these improvements were meaningful; this was indicated by their satisfaction and wish to continue receiving treatment. Ellen Freeman, the lead researcher of the study, comments “our findings suggest that among healthy women, 10–20 mg/day of escitalopram provides a nonhormonal, off-label option that is effective and well tolerated in the management of menopausal hot flashes”.

The group suggests further research is required to investigate the efficacy of SSRIs and SNRIs compared with hormonal therapy in the treatment of hot flashes in menopausal women.

Source: Freeman EW, Guthrie KA, Caan B et al.: Efficacy of escitalopram for hot flashes in healthy menopausal women: a randomized controlled trial. JAMA 305(3), 267–274 (2011).

Research group discuss benefits of robotic surgery

Researchers at the Jewish General Hospital (QB, Canada) have published two studies based on the clinical outcomes of their patients following robotic surgery for gynecological cancer. The studies, published in the Journal of Robotic Surgery and the International Journal of Gynecological Cancer, respectively conclude that robot-assisted surgery is cost effective when compared with the conventional laparoscopic approach, and results in good surgical outcomes and high quality-of-life scores.

“It's extremely beneficial for the patient”, comments Walter Gotlieb, Associate Professor at the Jewish General Hospital Segal Cancer Center, and one of the coauthors of the studies. “They can go home usually the next day, have very little pain and even the most complex cases – elderly patients – do very well”.

In the Journal of Robotic Surgery paper, Gotlieb and colleagues compared the cost to the hospital of performing an open radical hysterectomy with a robotic radical hysterectomy. They calculated that the average cost of the traditional surgical method was CAN$11,764, including hospital accommodation, surgeon and anesthetist fees, medications and other expenses, whilst the robot-assisted procedure cost an average of $9613. The researchers also calculated that the average cost per surgery would drop to $8898 if the robot were used on a high-volume basis. Although the robotic procedure takes longer to perform than traditional laparotomy, it was seen to result in a shorter hospital stay, less need for pain medications and reduced perioperative morbidity.

In the International Journal of Gynecological Cancer paper, the researchers compared the outcomes of 100 patients who underwent robotic surgery for endometrial cancer and how they differed amongst elderly (over 70 years) and younger (below 70 years) patients. They found that, although the elderly group had a significantly higher number of comorbidities and more advanced disease compared with the younger group, the health status of patients in these two groups were virtually the same after surgery, and differences seen in complication rates and length of hospital stay between the two groups were not statistically significant. The postoperative quality-of-life assessment revealed that patients in both age groups were highly satisfied with the procedure.

“Robotic hands are steadier than those of a human. Robotic arms also possess seven degrees of freedom or movement compared with a human arm's four degrees – up, down, left and right. This enables the surgeon to operate with much greater flexibility”, explains Gotlieb.

Sources: Vaknin Z, Perri T, Lau S et al.: Outcome and quality of life in a prospective cohort of the first 100 robotic surgeries for endometrial cancer, with focus on elderly patients. Int. J. Gynecol. Cancer 20(8), 1367–1373 (2010); Halliday D, Lau S, Vaknin Z et al.: Robotic radical hysterectomy: comparison of outcomes and cost. J. Robot. Surg. 4(4), 211–216 (2010); Jewish General Hospital; www.jgh.ca/en/newsroom/?id=747

in brief …

Amino acid-dependent activation of liver estrogen receptor A integrates metabolic and reproductive functions via IGF-1. Della Torre S, Rando G, Meda C et al.: Cell Metab. 13(2), 205–214 (2011). A recent study suggests that estrogen receptors in the liver are critical for maintaining fertility in women. The expression of the receptors is linked to dietary amino acids. The research, which was performed on mice, reported that expression of estrogen receptors is dependent on dietary amino acids. Mice given a calorie-restricted diet, and those lacking estrogen receptors in their liver, showed a decline in the hormone IGF-1. The levels of the hormone in blood reduced to levels that were inadequate for the correct growth of the uterus lining and normal progression of the estrous cycle. When the mice were given a diet higher in protein the reproductive cycles were restored. The study concluded that there is a connection between amino acids, estrogen signaling in the liver and reproductive function.

Age of onset of puberty predicts adult osteoporosis risk: later puberty results in lower bone mass. Gilsanz V, Chalfant J, Kalkwarf H et al.: J. Pediatrics 158(1), 100–105 (2011). An American study has determined that the onset of puberty was the primary influence on adult bone mineral density or bone strength, and that the length of puberty does not affect bone density. A total of 78 girls and 85 boys were studied, who had begun puberty and completed skeletal maturity 4–5 years later. Multiple linear regression analyses indicated that the age of onset of puberty was a strong negative predictor of bone mineral content and bone mineral density at skeletal maturity. These measurements were independent of bone values at the beginning of puberty, and the length of puberty. This negative trend was observed in both boys and girls, in all measurements at all skeletal sites. The study concluded that in healthy adolescent males and females, bone mass and bone density at skeletal maturity are inversely related to the timing of puberty.

Value of screening may be reduced by the biological diversity of ovarian cancer

Scientists working at Duke Cancer Institute, Durham, NC, USA, have indicated that including the latest information about the biological diversity of ovarian cancer may reduce the potential value of screening for the disease.

Ovarian cancer is a relatively rare disease that can progress while manifesting relatively few symptoms. This can result in late-stage detection, rendering potentially curative treatments useless. An effective screening technique for the disease has been elusive, as one of the most commonly used biomarkers in the screening process, CA125, is related to other disorders.

Ovarian cancer has, until now, been regarded as a single disease. However, this study and others have revealed that there are at least two subtypes of the disease. The subtypes identified are distinct from each other; the first is a slow, indolent form which can take months or years for the cancer to move to an advanced stage. However, the second subtype is more aggressive and is driven by a key gene mutation; this variety moves through stages I and II in approximately half the time of the slow-growing variety.

The researchers used information from the Surveillance, Epidemiology and End Results (SEER) database to create a decision model for ovarian cancer screening. The SEER database, which is maintained by the NIH, compiles information on prevalence, incidence and survival of cancer in the USA and categorizes ovarian cancer by type. The decision model was validated using data from the UK Collaborative Trial of Ovarian Cancer Screening. This large, randomized trial utilized CA125 values and ultrasound to screen postmenopausal women for the presence of ovarian cancer.

The model was then used to predict how much the percentage of cancer deaths could be reduced by screening women over the age of 50 years in the USA. The results indicated that when ovarian cancer was categorized as a single disease the cancer deaths could be reduced by approximately 15%. However, when the two subtype categorization was incorporated, the reduction was predicted as only 11%.

These results are expected, as screening is more likely to pick up a greater number of slow-growing tumors, as opposed to fast growing tumors. This is due to the indolent cancer remaining at a treatable stage for a longer time period than the more virulent, aggressive tumors. Laura Havrilesky, who led the study, comments “catching and successfully treating the slower-growing cancers isn't going to do as much to reduce deaths from ovarian cancer as catching the more lethal tumors would do.”

Source: Duke Cancer Institute Press release: www.dukehealth.org/health_library/news/biological-diversity-of-ovarian-cancer-lessens-value-of-screening