A new approach to create targeted nanovesicles for cancer treatment

Researchers have used autologous immune cells from the mouse to create nanovesicles to be used in the delivery of drugs to tumors. This technique helped them to create a sufficient number of nanovesicles inexpensively to be used as drug delivery system.

This image shows ligands-grafted extracellular vesicles as drug delivery vehicles.
Credit: Xin Zou 

Cells naturally release nanovesicles to carry chemical messages between cells. To create targeted nanovesicles, ligands (short pieces of protein) need to be attached to the nanovesicle wall so they can recognize tumor cells. This is done by incorporating DNA into cells and collecting extracellular nanovesicles from cell culture supernatant. However, the yield of nanovesicles is poor using above process. Researchers now developed a new approach by chemically grafting lipid tagged ligands to the cell membrane and then passing them through a seave to create large amounts of fillable and targeted nanovesicles.  Research findings are published in journal Cancer Research.

“Currently, natural nanovesicles can be harvested from cell culture supernatant (the fluid surrounding cultured cells) and they are fillable,” said Yuan Wan, a postdoctoral fellow in biomedical engineering, Penn State. “However, there are two problems using them for cancer treatment. There aren’t enough nanovesicles produced in short timescales and they do not have targeting effect.”

“Pushing the cells through a filter is the engineered way to produce lots of nanovesicles,” said Zheng. “This approach enables us to create nanovesicles with different ligands targeting different types of tumors in about 30 minutes to meet actual needs,” said Zheng. “With this approach, we also can put different types of ligands on a nanovesicle. We could have one ligand that targets while another ligand says, ‘don’t eat me.'”

Reference: Wan, Yuan, Lixue Wang, Chuandong Zhu, Qin Zheng, Guoxiang Wang, Jinlong Tong, Yuan Fang, Yiqiu Xia, Gong Cheng, Xia He, and Si-Yang Zheng. “Aptamer-Conjugated Extracellular Nanovesicles for Targeted Drug Delivery.” Cancer Research 78, no. 3 (2017): 798-808. doi:10.1158/0008-5472.can-17-2880.

Research funding: Nanjing Science and Technology Development Foundation, Jiangsu Provincial Medical Youth Talent Award, Natural Science Foundation of Jiangsu Province, U.S. National Institutes of Health.

Adapted from press release by Penn State.

Hemanthamine found in Daffodils has anti-cancer properties

Researchers from Université Libre de Bruxelles discover that alkaloid found in Daffodils has anti-cancer properties. This alkaloid called haemanthamine works by triggering activation of anti-tumor surveillance pathway. This study was led by Dennis Lafontaine and is published in journal Structure.

Structure of Ribosome. Credit ULB

Researchers found that this compound binds to the ribosome and blocks the production of proteins. Haemanthamine also inhibits the production of these ribosomes in the nucleolus. This nucleolar stress triggers the activation of an anti-tumoral surveillance pathway leading to the stabilization of the protein p53 and the elimination of cancer cells.

In the near future, the team of Denis Lafontaine, in collaboration with Veronique Mathieu (Faculty of Pharmacy- ULB), will test the effect on ribosome biogenesis and function of four Amaryllidaceae alkaloids, representative of the chemical diversity of these molecules. Their goal will be to identify the most promising chemical backbone to be further developed as a lead compound in cancer therapeutics.

Reference: Pellegrino, Simone, Mélanie Meyer, Christiane Zorbas, Soumaya A. Bouchta, Kritika Saraf, Stephen C. Pelly, Gulnara Yusupova, Antonio Evidente, Véronique Mathieu, Alexander Kornienko, Denis L.j. Lafontaine, and Marat Yusupov. “The Amaryllidaceae Alkaloid Haemanthamine Binds the Eukaryotic Ribosome to Repress Cancer Cell Growth.” Structure, 2018. doi:10.1016/j.str.2018.01.009.

Adapted from press release by Université Libre de Bruxelles.

New biomarker based on expression of SHOX2 gene for predicting survival in Gliomas

Researchers at UT Southwestern Medical Center have found a new biomarker for glioma, a common type of brain cancer, that can help doctors determine how aggressive a cancer is and that could eventually help determine the best course of treatment. The findings are published in EBiomedicine.

Researchers from the Harold C. Simmons Comprehensive Cancer Center found that high expression of a gene called SHOX2 predicted poor survival in intermediate-grade gliomas.  “As an independent biomarker, SHOX2 expression is as potent as the currently best and widely used marker known as IDH mutations,” said Dr. Adi Gazdar, Professor of Pathology in the Nancy B. and Jake L. Hamon Center for Therapeutic Oncology and a member of the Simmons Cancer Center.

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According to the National Cancer Institute, cancers of the brain and nervous system affect nearly 24,000 people annually. In 2013, there were an estimated 152,751 people living with brain and other nervous system cancer in the United States. The overall 5-year survival rate is 33.8 percent.
Knowing the probable survival status of an individual patient may help physicians choose the best treatment. In combination with IDH mutations or several other biomarkers, SHOX2 expression helped to identify subgroups of patients with a good prognosis even though other biomarkers had predicted a bad prognosis.

“Our findings are based on analysis of previously published studies. They will have to be confirmed in prospective studies, and their clinical contribution and method of use remain to be determined,” said Dr. Gazdar, who holds the W. Ray Wallace Distinguished Chair in Molecular Oncology Research.

Citation: “SHOX2 is a Potent Independent Biomarker to Predict Survival of WHO Grade II–III Diffuse Gliomas”. Yu-An Zhang1, Yunyun Zhou1, Xin Luo, Kai Song, Xiaotu Ma, Adwait Sathe, Luc Girard, Guanghua Xiao and Adi F Gazdar. EBioMedicine 2016 vol: 13 pp: 80-89.
DOI: 10.1016/j.ebiom.2016.10.040
Research funding: NIH
Adapted from press release by UT Southwestern Medical Center.

Research identifies protein behind side effects of cellular senescence

Cellular senescence is a state in which normal healthy cells do not have the ability to divide. Senescence can occur when cancer-causing genes are activated in normal cells or when chemotherapy is used on cancer cells. Thus, senescence induces a mechanism that halts the growth of rapidly dividing cells. Once thought to only be beneficial to halt cancer progression, work from the The Wistar Institute has shown that during senescence there is an increase in secreted factors called cytokines and chemokines (small proteins important in immune responses) that may have detrimental, pro-tumorigenic side effects.

Researchers at The Wistar Institute have identified a protein that plays a critical role in the expression of cytokines and chemokines, and that decreasing this protein suppresses the expression of these secreted factors. This suggests that there may be ways of promoting the positive effects of senescence while suppressing its negative effects. The findings were published online by the Journal of Cell Biology.

Rugang Zhang, Ph.D., professor and co-program leader of the Gene Expression and Regulation program at Wistar, and colleagues focused on chromatin, a cellular structure responsible for holding the DNA in our cells together. During senescence, some of the chromatin is reorganized into senescence-associated heterochromatin foci (SAHF). When this happens, genes that are responsible for promoting proliferation are silenced. However, the expression of cytokine and chemokine genes  known collectively as the senescence-associated secretory phenotype (SASP) is increased.

“When senescence happens, you have two closely linked phenomena occurring, yet one of these helps to halt tumor progression while the other causes an increase in potentially harmful inflammatory cytokines and chemokines,” said Zhang, who is lead author of the study. “We pinpointed the architecture of chromatin and the proteins that influence chromatin organization as the proper place to start to try and solve this paradox.”

The scientists looked at a set of proteins known as high mobility group proteins, which are responsible for altering chromatin architecture in order to regulate gene transcription. One such protein called high mobility group box 2 (HMGB2) binds to DNA to increase chromatin’s accessibility to transcription factors. They showed that high mobility group box 2 (HMGB2) promotes senescence-associated secretory phenotype (SASP) gene expression by preventing the spreading of heterochromatin and therefore preventing senescence-associated heterochromatin foci (SAHF) from silencing senescence-associated secretory phenotype (SASP) genes. When the researchers silenced high mobility group box 2 (HMGB2), senescence-associated secretory phenotype (SASP) genes were successfully silenced by SAHF, suggesting that the detrimental effects of senescence might be negated by inhibiting high mobility group box 2 (HMGB2).

“Understanding senescence is critical for understanding how tumor growth can be successfully suppressed,” said Katherine Aird, Ph.D., a staff scientist in the Zhang lab and first author of the study. “With the information from this study, we may be able to increase the effectiveness of chemotherapeutic agents that are able to induce senescence by silencing high mobility group box 2 (HMGB2) and decreasing the expression of unwanted secreted factors.”

Citation: HMGB2 orchestrates the chromatin landscape of senescence-associated secretory phenotype gene loci. Katherine M. Aird, Osamu Iwasaki, Andrew V. Kossenkov, Hideki Tanizawa, Nail Fatkhutdinov, Benjamin G. Bitler, Linh Le, Gretchen Alicea, Ting-Lin Yang, F. Brad Johnson, Ken-ichi Noma, Rugang Zhang. Journal of Cell Biology Oct 2016, jcb.201608026;
DOI: http://dx.doi.org/10.1083/jcb.201608026
Research funding: National Institutes of Health, NIH/National Cancer Institute, Ovarian Cancer Research Fund Alliance, The Jayne Koskinas & Ted Giovanis Breast Cancer Research Consortium at Wistar, Russian Government Program.
Adapted from press release by The Wistar Institute