Single Catastrophic Event Can Lead to Cancer

Image: Flickr - Mohamed Hussain
Development of cancer is conventionally viewed as a gradual process, taking years to accumulate multiple point mutations and chromosomal rearrangements, and progressing through increasingly malignant phenotypes. New research by a team at the Wellcome Trust Sanger Institute has shown that, in some cases, cancer can result from a single catastrophic event involving tens to hundreds of genomic rearrangements. Using advanced DNA sequencing techniques, the team found that 2-3% of cancer samples, across many common subtypes, had dramatic structural changes affecting highly localised regions of one or more chromosomes that could not be explained using standard models of DNA damage. This type of damage was especially common in bone cancers, where around 25% of samples showed signs of chromosomal crisis.

The team have proposed that such extensive damage is likely to occur when the chromosomes are condensed for mitosis and could be caused by ionising radiation or linked to telomere attrition. If the cell attempts to repair such extensive damage, the evidence suggests that the repair goes badly wrong, resulting in a genome that is riddled with mutations. In most cases, such haphazard repairs would be detrimental to the cell’s ability to survive and divide but in some cases can amplify cancer genes or inactivate tumour suppressor genes. It is remarkable that the cell can not only survive such a cataclysmic event but can emerge with a selective advantage.

The study is published in the journal, Cell.

A Closer Look at the Immune Response to Cancer Cells

Leukocytes: Friend or Foe to Transformed Cells? Image of a neutrophil (red) gliding over a doublet of transformed mucus-producing cells
Last week it was reported that a daily (low) dose of aspirin can significantly reduce the risk of dying from a variety of cancers, and a study published in PloS Biology now opens a new window on the role of inflammation in cancer.

Although the host immune system is known to have conflicting roles in cancer initiation and progression, both acting as a surveillance and elimination system but also assisting expansion and metastatic spread of tumours, very little is known about the very early role of the immune system in cancer. Using zebrafish larvae, researchers at the University of Bristol, the University of Manchester and the FIRC Institute of Molecular Oncology in Milan have now been able to observe, for the first time, how oncogene-transformed cells in the skin co-opt the innate immune system to promote their growth from the very earliest stages of development. The team exploited the translucency of the larvae to obtain live images of the earliest interactions between the cancer cells and the immune environment. Using larvae with fluorescently tagged leukocytes, the team were able to observe recruitment of neutrophils and macrophages to oncogene-transformed melanocytes or mucus-secreting cells. As well as engulfment of the transformed cells, the team saw many examples of cytoplasmic tethers linking the two cell types.

They discovered that a key attractant for the leukocytes was hydrogen peroxide. Both the transformed cells themselves and otherwise healthy neighbouring cells were found to produce hydrogen peroxide, which is also a key molecule that recruits neutrophils to a wound. Blocking the synthesis of hydrogen peroxide prevented recruitment of immune cells and reduced the number of transformed cells, suggesting that immune cells may provide trophic support to the transformed cells just as they promote repair at a site of tissue injury. Unlike the case of wound healing, however, where the inflammatory response resolves, the inflammatory response to transformed cells seems to amplify and progress towards a chronic inflammatory state similar to that seen in chronic non-healing wounds.

Blocking Faulty Replication Could Boost Response to Chemotherapy

Image: Flickr - Mark Cummins
Many chemotherapy drugs, including cisplatin, cause damage to DNA and kill cancer cells by interfering with DNA replication and cell division. The damage activates cellular DNA repair mechanisms but, if the damage is too extensive, the cell undergoes apoptosis. Unfortunately, although the initial response to cisplatin is generally good, the majority of tumours will eventually develop resistance to the drug. Resistance can develop when the cell is able to replicate DNA through damaged regions using a translesion synthesis (TSL) DNA polymerase. This type of DNA replication is highly error-prone, introducing mutations into the DNA which can drive drug resistance. Suppressing the ability of tumour cells to replicate damaged DNA using the translesion synthesis DNA polymerase, Polζ has been shown to block resistance to cisplatin in human cancer cells grown in culture and now, in two papers published in PNAS, researchers at the Massachusetts Institute of Technology have shown that the approach also works in mice.

The first paper describes a tumour transplantation approach to examine the effect of impaired translesion DNA synthesis on cisplatin response in aggressive late-stage lung cancers. The researchers used RNA interference to reduce levels of Rev3, an essential component of Polζ, and showed that a 60-70% reduction doubled survival time in cisplatin-treated animals. The team also showed that Rev3-deficient cells showed reduced cisplatin-induced mutations which have been suggested to contribute to secondary malignancies following chemotherapy.

In the second study, the researchers used a mouse model of B-cell lymphoma to show that suppressing Rev1, an essential TSL scaffold protein and dCMP transferase, inhibits both cisplatin- and cyclophosphamide-induced mutagenesis. By performing repeated cycles of tumor engraftment and treatment, the team were also able to show that Rev1 plays a critical role in the development of acquired cyclophosphamide resistance.

The studies show that chemotherapy can not only select for drug-resistant populations of tumour cells but can also directly promote the acquisition of resistance-causing mutations, suggesting that blocking translesion DNA polymerases may have dual anticancer effects by both increasing the sensitivity of tumours to chemotherapy as well as reducing the potential for emergence of drug resistance during treatment. The next challenge will be to identify inhibitors of the translesion DNA polymerases.

FSH Receptors Outline Tumours

silver lining
Image: Flickr - dewet
Researchers at Mount Sinai School of Medicine and France’s National Institute of Health and Medical Research (INSERM) have discovered a biomarker that could be applicable to a range of different cancers.

In a study of more than 1300 patients, the team found that the follicle stimulating hormone (FSH) receptor – which is normally present only at low levels in the blood vessels or the granulosa cells of the ovary and the Sertoli cells of the testis – is also expressed at higher levels in eleven different types of cancer. The receptor was absent in other normal tissues, including normal tissue from the organ bearing the tumour. Not only does the FSH receptor appear to be specific for endothelial cells in the vasculature surrounding tumour tissues, it is also present from the very early stages and is easily detectable using conventional imaging methods. In most cases, the blood vessels expressing FSH receptors were at the periphery of the tumour, in a layer about 10mm thick, making it a good target for improving cancer detection and also guiding surgery and radiation treatment. Blocking FSH receptor signalling, which stimulates angiogenesis via up-regulation of vascular endothelial growth factor, could also potentially provide a new strategy for developing anticancer drugs.

The study is published in The New England Journal of Medicine.

Blocking Cancer Networks

spider web
Image: Flickr - Luc Viatour
The emergence of drug resistance is one of the main causes of failure in cancer treatment and is one reason that cancer drugs are often used in combination. Resistance can also arise during the use of combinations of cytotoxic agents developed by trial and error but researchers at Fox Chase Cancer Center and Georgetown University have now developed a better way of selecting drug combinations based on molecular targets.

The epidermal growth factor receptor (EGFR) is a well validated molecular target and inhibitors are already used clinically for certain types of cancer. The team used siRNA to silence 638 genes known to encode proteins involved in the EGFR signalling network and identified over 60 proteins that can rescue cells in the presence of an EGFR inhibitor. Amongst these were three proteins for which drugs are already being developed: Aurora kinase A, protein kinase C, and STAT3. Aurora kinase A inhibitors are already being evaluated clinically and a trial testing the EGFR inhibitor erlotinib with an Aurora kinase inhibitor in patients with non-small cell lung cancer is being launched. A similar network-centred approach could be used to design other combination therapies to overcome resistance mechanisms in cancer.

Interestingly, the screen did not pick out genes previously linked to resistance to EGFR inhibitors and most of the genes identified were not mutated: KRAS mutations did not appear to be needed for resistance to EGFR inhibitors although patients with KRAS mutations do not benefit from EGFR inhibitors.

The study is published in Science Signaling.

The BMK1 Pathway in Oncology – a Road Less Travelled

Image: Flickr – Zach Chisholm
Of the four mammalian MAP kinase pathways (ERK1/2, JNK, p38 and BMK1), BMK1 is the least studied. BMK1 and ERK1/2 pathways are both activated by mitogens and oncogenic signals and are therefore implicated in tumorigenesis. Indeed, the ERK1/2 pathway has received significant attention for the development of chemotherapeutic drugs. Deregulated BMK1 activity has been associated with a variety of human malignancies including chemoresistance of breast tumours, metastasis of prostate tumour cells and tumour-associated angiogenesis. Conditional knockout of endothelial BMK1 in mice, however, led to lethal vascular instability, discouraging exploration of BMK1 as a therapeutic target.

XMD8-92 structure
A new study from scientists at the Scripps Research Institute has revealed more detail on the role of BMK1 in oncogenesis and suggests that BMK1 inhibition could be a viable therapeutic strategy. The study found that BMK1 is associated with the tumour suppressor, PML (promyelocytic leukemia protein), and suppresses its anti-cancer activity. In cellular studies, reduced expression of BMK1 resulted in induced expression of p21, a downstream effector of PML and modulator of cell proliferation.

The team’s serendipitous discovery of a selective inhibitor of BMK1, XMD8-92, permitted further studies in animal models. XMD8-92 significantly inhibited the growth of xenografted human tumours in mice, with no obvious adverse effects. More specifically, in contrast to the BMK1 conditional knockout studies, no vascular instability was observed in response to pharmacological inhibition of BMK1.

The study is published in Cancer Cell.

Decoy Receptor Reverses Cancer Cachexia, Improves Survival in Mice

duck decoys
Image: Flickr - vhhammer
Debilitating muscle wasting or cachexia affects the majority of patients with advanced cancer but although the condition is believed to contribute to cancer-related deaths, the precise mechanisms by which cancer causes cachexia and those by which cachexia contributes to a poor prognosis are ill understood. There are currently limited treatment options for patients with cachexia, but scientists at Harvard Medical School and Amgen Research have now created a decoy receptor that can reverse cachexia in mice and increase survival, even though it has no effect on tumour growth.

ActRIIB is a high affinity activin type 2 receptor that mediates signalling by a subset of TGF-β family ligands, including myostatin, which inhibits muscle cell differentiation and growth, and activin, which is abundant in some cancer patients. Activation of ActRIIB initiates a signalling cascade that leads to increased degradation of myofibrillar proteins through the ubiquitin-proteasome pathway. In several mouse models of cachexia, administration of soluble ActRIIB (sActRIIB) was found not only to prevent further wasting but also to fully reverse both skeletal muscle loss and atrophy of the heart. Treatment with sActRIIB had no effect on fat mass or tumour growth and did not reduce elevated inflammatory cytokines, although it did stimulate feeding.

The study, which is published in the journal Cell, suggests that blocking the ActRIIB pathway has the potential to treat various muscle wasting diseases, particularly cancer cachexia, and if the results of the mouse studies translate to people, could also prolong the lives of cancer patients.

Mouse T-cells Could Help in Fight Against Human Cancer

Mouse Biplane
Image: Wikimedia Commons - Wilfredor
T-cell receptors are integral membrane proteins that recognise foreign antigens and initiate a series of intracellular signalling cascades that allow the immune system to fight infection. To avoid autoimmune diseases, T-cells must be able to discriminate between ‘self’ and ‘foreign’ antigens but this discrimination may also prevent the immune system from recognising and destroying tumour cells.

Researchers led by a team from the Max-Delbrück-Center for Molecular Medicine have now developed transgenic mice that produce T-cell receptors that recognise human cancer cell antigens and could potentially be introduced into the T cells of cancer patients. Using embryonic stem cells loaded with human DNA, the team generated transgenic mice that express the entire human T-cell repertoire. Negative selection normally removes maturing T-cells that are capable of binding strongly to ‘self’ antigens but the mouse does not recognise human cancer cell antigens as ‘self’ and T-cells expressing receptors to these antigens are allowed to survive. T-cells with such high affinity receptors for cancer cell antigens are not produced in humans and the researchers hope that introducing the high affinity receptors into the T-cells of cancer sufferers will boost the immune system’s ability to recognise and destroy tumour cells. A first clinical trial to evaluate the efficacy and tolerability of the methodology in cancer patients is planned.

The study is published in the journal Nature Medicine.

Arsenic Gets Nanotechnology Treatment

arsenic trioxide model
Molecular model of arsenic trioxide as found in the mineral arsenolite. Source: Wikipedia – Ben Mills
Despite its reputation as a poison, arsenic has long been used in Chinese medicine and, more recently, arsenic trioxide has been successfully used to treat acute promyelocytic leukaemia (APL). The drug has poor activity against solid tumours, however, probably because it is rapidly excreted. Attempting to address this, researchers at Northwestern University have packaged arsenic trioxide in nanoparticles.

These nanoparticles, termed nanobins, are composed of nanoparticulate arsenic trioxide encapsulated in liposomes. A second chemical layer provides protection for both the cargo and normal cells until the particle reaches its target. The nanoparticles concentrate at their target, as a consequence of the leaky blood vessels that characterise solid tumours, and release their toxic payload.

In the current study, published in Clinical Cancer Research, the researchers investigated the activity of arsenic nanobins against a panel of human breast cancer cell lines. Although less cytotoxic than free arsenic trioxide in vitro, the nanobins had dramatically enhanced efficacy in an in vivo model of triple-negative breast cancer. The scientists observed reduced plasma clearance, increased tumour uptake and induction of tumour cell apoptosis for the nanobins.

Triple negative breast cancer, in which the receptors for oestrogen, progesterone and Her2 are absent, is an aggressive cancer that often responds poorly to conventional chemotherapy. There is a high risk of metastatis and survival rates are low. Although at an early stage, the researchers anticipate that the nanobin technology could provide the means to increase the efficacy of a number of cytotoxic drugs against a range of tumours, whilst reducing general toxicity.

Mild Stress Could Reduce Cancer

Image: Flickr - árticotropical
Whilst the effects of social and environmental factors on many aspects of health are relatively well understood, their influence on the progression of systemic cancer is much less well defined. A team of investigators led by scientists at The Ohio State University have now investigated the effect of an enriched environment – a more challenging setting that causes mild stress – on the growth of cancer in mice. The study found that an enriched environment – consisting of more complex housing, regular exposure to novel objects, and more exercise and social stimulation – led to a remarkable suppression of cancer proliferation in models of melanoma and colon cancer, even if delayed until the tumour was well established.

The researchers went on to identify the molecular pathways involved and discovered the enriched environment led to activation of a system known as the hypothalamic-sympathoneural-adipocyte (HSA) axis by brain-derived neurotrophic factor (BDNF). Activation of the HSA axis is proposed to increase sympathetic nervous system outflow to adipocytes, resulting ultimately in reduced secretion of leptin and increased secretion of adiponectin. The β-blocker, propanolol, was shown to inhibit the changes in circulating levels of leptin and adiponectin brought about by an enriched environment and also to block the inhibition of tumour growth, suggesting a link between β-adrenergic activity in white adipose tissue, circulating leptin/adiponectin levels and tumour growth.

The researchers propose that adipokines, released by white adipose tissue in response to hypothalamic BDNF-induced sympathetic outflow caused by mild stress, act as the major downstream effectors of a complex regulatory network leading to the antiproliferative phenotype. Direct gene transfer of BDNF was found to mimic the beneficial effects of an enriched environment, suggesting that either pharmacological or environmental induction of hypothalamic BDNF could slow the growth of tumours.

The study is published in the journal Cell.