Tuesday 18 June 2013

Brief: A test for potentially harmful human induced pluripotent stem cells

Yamashita et al. have produced a method for determining if human induced pluripotent stem cells (iPSC) are likely to form tumours and published their results in Scientific Reports.

Taking a patient's cells, engineering them to gain stem cell properties, such as being able to self-renew and develop into multiple different cell types, and re-injecting them into that patient's tissue is an emerging new therapeutic field. However there are concerns that these cells, once transplanted into a patient, may become cancerous. The methods used to make human iPSCs often involves making normal cells express stem cell factors (which in themselves can be oncogenic - cancer forming) and the oncogene c-myc.

By making these iPSCs into cartilage and monitoring for the formation of tumours, the group could see which iPSCs were potentially harmful. This test could prove crucial in validating iPSCs for regenerative medicine.

Mentioned Articles

Yamashita A, Liu S, Woltjen K, Thomas B, Meng G, Hotta A, Takahashi K, Ellis J, Yamanaka S, Rancourt DE.
Sci Rep. 2013 Jun 13;3:1978. doi: 10.1038/srep01978.

Sunday 16 June 2013

Micro-RNAs and Retinoic Acid take their Toll on prostate and breast cancer

One of the first lines of defence against infection is the innate immune system. This mounts a non-specific response to infectious agents including bacteria and viruses. Recognition of bacterial and viral components is accomplished by a family of receptors called Toll Like Receptors (TLRs) found on the surface of innate immune cells. TLRs can also be expressed by other cells such as cancer cells.

Previous studies have shown that activation of TLRs can affect the levels of micro RNAs (miRNAs) in cells and therefore regulate which proteins are expressed (I have mentioned the role of miRNAs in cancer in previous posts). In this present study, Galli et al. found that activation of TLR3 in prostate and breast cancer cells caused an increase in four miRNAs. These miRNAs target a class of proteins called DNA methyltransferases, resulting in the loss these proteins from the cancer cells. Without these DNA methyltransferases a protein called retinoic acid receptor beta (RARβ) is produced by the cancer cells.

In a breakthrough, the group showed that drugging tumours first with an activator of TLR3 followed by retinoic acid (an activator of RARβ), caused tumours to be smaller compared to control treated tumours. This study therefore presents promising pre-clinical data for the treatment of breast and prostate cancer with this exciting combination therapy.

Mentioned Articles

Galli R, Paone A, Fabbri M, Zanesi N, Calore F, Cascione L, Acunzo M, Stoppacciaro A, Tubaro A, Lovat F, Gasparini P, Fadda P, Alder H, Volinia S, Filippini A, Ziparo E, Riccioli A, Croce CM.
Proc Natl Acad Sci U S A. 2013 Jun 11;110(24):9812-7. doi: 10.1073/pnas.1304610110. Epub 2013 May 28.

Chen R, Alvero AB, Silasi DA, Steffensen KD, Mor G.

Oncogene. 2008 Jan 7;27(2):225-33. doi: 10.1038/sj.onc.1210907.

Friday 14 June 2013

Researchers hot on the TRAIL of new combination therapy for glioblastoma

Some cancers are particularly difficult to treat, particularly brain tumours. Glioblastoma is an aggressive form of cancer in the brain which, although responds initially to treatment, is refractory and often always fatal. Treating cancerous cells with a protein called TRAIL is a specific treatment which causes cancer cell death in around 50% of cancer cell lines. Bagci-Onder et al. employ some interesting molecular techniques to studying the effect of TRAIL on glioblastoma cell viability.

Neuronal stem cells were used to deliver soluble TRAIL protein to glioblastoma cells and the way in which this happens was modelled by artificially colouring both cell types and watching their interactions when grown together. Two out of three glioblastoma cell lines tested were sensitive to TRAIL treatment and underwent a form of highly controlled cell death called apoptosis.

The killing of these cells by TRAIL treatment was dependent on the levels of two proteins on the cell surface called death receptors; death receptor 4 (DR4) and death receptor (DR5). The group observed that the higher the levels of these receptors, the more receptive to TRAIL treatment the cells were. This led the group to postulate that increasing death receptor expression could enhance the effectiveness of TRAIL in treating glioblastoma.

To see how they could increase death receptor expression in cancerous cells, the group used a panel of different drugs known to affect the way cells function. They found that targeting histone deacetylases (HDACs) [see previous post] with a drug called MS-275 caused an increase in death receptor levels at the surface of cells. As expected, this also led to an increased sensitivity to TRAIL treatment. Importantly, the one glioblastoma cell line which was initially resistant to TRAIL treatment became sensitive to the killing power of TRAIL if cells were also treated with MS-275. This study highlights a potential new combination treatment for glioblastoma.

Mentioned Articles

Bagci-Onder T, Agarwal A, Flusberg D, Wanningen S, Sorger P, Shah K.

Oncogene. 2013 Jun 6;32(23):2818-27. doi: 10.1038/onc.2012.304. Epub 2012 Jul 23.

"Types of primary brain tumours : Cancer Research UK : CancerHelp UK." Cancer Research UK: the UK's leading cancer charity : Cancer Research UK . N.p., n.d. Web. 13 June 2013.