Apoptosis to Accelerate Tumor Growth

Inducing cells apoptosis has always been considered one way to cure cancer. However, according to the latest research, it may not be that simple. Through the study on lymphoma and melanoma, scientists from UK has found that apoptotic cells could accelerate the growth of cancer cells and the assemble and vasculogenesis of tumor-associated macrophages TAM. The study was published in Current Biology.

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Cells undergoing apoptosis are known to modulate their tissue microenvironments. By acting on phagocytes, notably macrophages, apoptotic cells inhibit immunological and inhibit immunological and inflammatory responses and promote trophic signaling pathways. Paradoxically, because of their potential to cause death of tumor cells and thereby militate against malignant disease progression, both apoptosis and tumor-associated macrophages(TAMs) are often associated with poor prognosis in cancer.

In this study, researchers demonstrate that apoptotic tumor cells promote coordinated tumor growth, angiogenesis, and accumulation of TAMs in aggressive B cell lymphomas. Through unbiased “in situ transcriptomics” analysis-gene expression profiling of laser-captured TAMs to establish their activation signature in situ. They show that these cells are activated to signal via multiple tumor-promoting reparatory, trophic, angiogenic, tissue remodeling, and anti-inflammatory pathways.

The research also shows that apoptotic lymphoma cells help drive this signature. Furthermore, they demonstrate that ,upon induction of apoptosis, lymphoma cells not only activate expression of the tumor-promoting matrix metalloproteinases MMP2 and MMP12 in macrophages but also express and process these MMPs directly.

These results have important implications for understanding the fundamental biology of cell death, its roles in malignant disease, and the broader consequences of apoptosis-inducing anti-cancer therapy.

Reference:

Ford C A, Petrova S, Pound J D, et al. Oncogenic Properties of Apoptotic Tumor Cells in Aggressive B Cell Lymphoma[J]. Current Biology, 2015, 25(5): 577-588.

New immunotherapy drug ‘fast-tracked’ for melanoma patients

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A new immunotherapy drug, pembrolizumab, has become the first treatment ‘fast-tracked’ for NHS patients with advanced melanoma, under a new Government scheme. Clinical trials have shown that it has the potential to ease symptoms and extend survival. The drug, also known as Keytruda, is the first to be signed off through the Early Access to Medicines Scheme (EAMS) , which aims to get pioneering drugs to severely ill patients much sooner.

Clinicians in the UK can now apply to prescribe the drug before normal European licensing procedures are complete, a process that can take years. Immunotherapy drugs are showing considerable promise in clinical trials with cancer patients. They work by interfering with the way cancer cells use signals to hide from the body’s immune system.

Some cancer cells send a message to the body’s immune cells, which tricks them into thinking these are normal body cells. Pembrolizumab, which is an antibody, locks on to a molecule on the surface of the immune cells that receives these messages – called PD-1. It blocks the signal from getting through, allowing immune cells to recognise the disease once again. Much of the research in understanding the role of PD-1 in cancer was carried out in the US.

However, a key step in the drug’s development – developing the antibody into a form that doesn’t itself get recognised and destroyed by the immune system – was carried out by UK scientists working for the Medical Research Council (MRC).

Dave Tapolczay, Chief Executive Officer of MRC Technology said: “We are very proud of our role in bringing this new cancer treatment to patients. Making Keytruda available under the Early Access to Medicines Scheme (EAMS) is another big step in getting healthcare innovation to patients sooner, and underlines our commitment to improving lives through science.”

Pembrolizumab becomes the second immunotherapy for cancer approved in recent years, following the approval in 2012 of ipilimumab, also for melanoma. Studies suggest the two drugs could be even more effective in combination, potentially alongside radiotherapy. Cancer Research UK head of policy, Emma Greenwood, said the announcement highlighted the great progress in developing immune treatments for cancer.

“It’s encouraging to see it being made available to patients earlier. NICE and the Cancer Drugs Fund only look at licensed drugs, so it’s a step in the right direction in terms of patients getting access to new treatments faster. “With this approach, relevant data will be collected and patients are closely monitored. We look forward to seeing whether it can be replicated with other promising drugs,” she added.

Researchers map the first ‘Genomic landscape’ of childhood adrenocortical tumors

A new paper, published in the journal Nature Communications, reports that researchers have mapped the “genomic landscape” of these rare childhood tumors. The discovery could lead to better identification of malignant pediatric adrenocortical tumors, and ultimately to better treatment.

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The first genomic mapping of childhood adrenocortical tumors has revealed unprecedented details of the aberrant genetic and chromosomal changes that drive the cancer. Understanding these data that drives tumors is critical because of the difficulty in reliably classifying which childhood adrenocortical tumors would prove to be malignant. Currently, about half of children with these tumors remain cancer-free after treatment, and those with advanced cancers have very poor overall survival.

The new mapping would offer a clue for identifying good markers to establish a prognosis. Searching good markers is a key point to predict the risk of cancer, which broaden the normal concept where larger tumors have a worse outcome than smaller ones.

Key mutations pinpointed

A participant said, “Pediatric adrenocortical tumors had never been analyzed on a genomic scale before. After sequencing the genomes of the tumor and blood samples from the 37 patients with early-to-late stage disease, my team pinpointed key mutations involved in these tumors as well as their timing in cancer development.

One key genetic mutation was found in the gene called TP53, which stands on chromosome 17p. TP53 acts as a “brake” on cell division under stress conditions, so its inactivation by mutation would unleash the uncontrolled proliferation of cancer cells.

A key molecular event uncovered by the study occurs on chromosome 11. This chromosome harbors a gene called IGF2, which expresses a protein from the paternal allele that promotes cell growth. Analysis of genomic DNA revealed the selective loss of the maternal chromosome 11 and duplication of paternal chromosome 11 in the pediatric adrenocortical tumors, leading to the continuous high expression of the IGF2 protein and abnormal cell growth.

With the chromosome 11 abnormality plus the TP53 mutation, the patients would be lost the brakes and stepped on the accelerator at the same time. Additionally, the genomic analysis also yielded the timing of these molecular events, the chromosomal 17 and 11 abnormalities, for instance, occurred early in tumor development, indicating a fundamental role for these genetic alterations in triggering tumor development.

Determining the prognosis

The genetic and chromosomal data on the cancers’ genetic landscape offer a highly promising research pathway to understanding the biology and evolution of childhood adrenocortical tumors. This research focuses on determining whether the genomic abnormalities distinguished by researchers have clinical value in determining the prognosis for these tumors.

In particular, the research team wants to confirm in a larger group of patients that a specific combination of mutations in genes called ATRX and TP53 do lead to more aggressive tumors with poorer prognosis.

The researchers said their studies may also lead to insights into other childhood cancers that also show deregulation of chromosome 11 and over-activity of IGF2, such as rhabdomyosarcoma, Wilms tumor and hepatoblastoma.

The findings also offer considerable promise for improving the treatment of childhood adrenocortical tumors. The study reveals tumor cases with more chaotic molecular changes that will require a different treatment approach.  A key to improving treatment will be using the new genomic knowledge to develop mouse models that would enable more systematic testing, not only of existing therapies, but new ones.

Reference

Genomic landscape of paediatric adrenocortical tumours. Nature Communications, 2015; 6: 6302

The scientist from China found a new tumor suppressor

CYP3A5 is a cytochrome P450 protein that functions in the liver metabolism of many carcinogens and cancer drugs. However, it has not been thought to directly affect cancer progression.

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In this study, the researcher challenge this perspective by demonstrating that CYP3A5 is downregulated in many hepatocellular carcinomas (HCC) where it has an important role as a tumor suppressor that antagonizes the malignant phenotype. CYP3A5 was downregulated in multiple cohorts of human HCC examined. Lower CYP3A5 levels were associated with more aggressive vascular invasion, poor differentiation,shorter time to disease recurrence after treatment and worse overall patient survival. Mechanistic investigations showed that CYP3A5 overexpression limited MMP2/9 function and suppressed HCC migration and invasion in vitro and in vivo by inhibiting AKT signaling. Notably, AKT phosphorylation at Ser473 was inhibited in CYP3A5-overexpressing HCC cells, an event requiring mTORC2 but not Rictor/mTOR complex formation. CYP3A5-induced ROS accumulation was found to be a critical upstream regulator of mTORC2 activity, consistent with evidence of reduced GSH redox activity in most clinical HCC specimens with reduced metastatic capacity.

Taken together, the results defined CYP3A5 as a suppressor of HCC pathogenesis and metastasis with potential utility a prognostic biomarker.

Reference:

Feng Jiang, Lei Chen, et al. CYP3A5 Functions as a Tumor Suppressor in Hepatocellular Carcinoma by Regulating mTORC2/Akt Signaling [J].2015(10).0008-5472.

New Mechanism on Cancer Metastasis

Scientists from Montreal Neurological Institute and McGill University have accomplished a new finding: one universal protein in human cells may be a key switch that could activate cancer cell metastasis. This finding is largely ignored so far. The finding of this protein expands our knowledge on epithelioma such as breast cancer and lung cancer. This study was published in JCB.

Rab  GTPases are master regulators of membrane trafficking controlling the formation of vesicles, vesicle transport via the actin and microtubule cytoskeletons, and vesicle tethering and fusion. Rabs are activated by guanine-nucleotide exchange factors(GEFs) that catalyze the exchange of GDP for GTP. The DENN(differentially expressed in normal and neoplastic cells) domain is an evolutionarily ancient and structurally conserved protein module.

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Currently, there are 26 identified DENN domain proteins, the majority of which are poorly characterized. One such protein, DENND2B, is a member of the DENND2A-D subfamily that contains a C-terminal DENN domain but few other distinguishing features. DENND2B was originally identified by screening a cDNA expression library for gene products that suppress the tumorigenicity of HeLa cells in nude mice and was named ST5.

In this study, researchers demonstrate that DENND2B localizes to the cell surface in association with the actin regulatory protein MICAL-L2, a Rab13 effector that induces membrane ruffles when bound to active Rab13. They develop and optimize a novel Forster resonance energy transfer(FRET)-based Rab13 biosensor that reveals selective activation of Rab13 on membrane ruffles at the dynamic leading edge of migrating cells, and they demonstrate that Rab13 activation by DENND2B at the cell surface is required for cell migration and invasion.

Finally, they find that disruption of the Rab13-DENND2B trafficking pathway dramatically reduces the migration of highly aggressive breast cancer cells in vivo. These findings provide evidence for a DENND2B-centered module that appears critical for the metastasis of cancer cells.

Reference:

Ioannou M S, Bell E S, Girard M, et al. DENND2B activates Rab13 at the leading edge of migrating cells and promotes metastatic behavior[J]. The Journal of cell biology, 2015, 208(5): 629-648.

Key Protein on Tumor Recurrence Identified

Recurrence is the main cause of death after tumor treatment. Tumor cells remain inactive and are activated again with more aggressively. This phenomenon has been one of the biggest mystery of tumor. Researchers from University of California San Francisco have identified the key protein HIGD1A in this process. The study was published in Cell Reports.

Hypoxia inducible factor(HIF-1) is a widely expressed transcription factor that regulates the survival of cells during oxygen and glucose deprivation. HIF can also regulate tumor metabolism by repressing respiration while promoting glycolysis, which enables rapid tumor cell proliferation.

It has been confirmed that some of the most metabolically compromised tumor regions found around their necrotic cores fail to induce HIF activity, potentially due to glucose starvation. Interestingly, these regions still express the HIF-1 target HIGD1A.

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In this study, scientists found that HIGD1A interacts with the mitochondrial electron transport chain, modulates oxygen consumption, ROS production, and AMPK activity to promote cell survival during glucose starvation, while simultaneously suppressing tumor growth invivo. Their studies confirm these observations and identify HIGD1A as an important upstream component of this signaling cascade. Furthermore , HIGD1A repression is associated with tumor recurrence in breast cancers following therapy, consistent with their observations that HIGD1A expression helps repress tumor growth.

These findings therefore provide novel insights into tumor cell adaptation mechanisms to extreme environments and suggest that HIGD1A may play an important role in tumor dormancy or recurrence mechanisms.

Reference:

 Ameri K, Jahangiri A, Rajah A M, et al. HIGD1A Regulates Oxygen Consumption, ROS Production, and AMPK Activity during Glucose Deprivation to Modulate Cell Survival and Tumor Growth[J]. Cell reports, 2015, 10(6): 891-899

Sneaky ‘nanobeacon’ delivers smackdown to cancer cells’ defenses

By silencing a mechanism that allows cancer cells to reject anti-cancer drugs, a new breakthrough out of MIT and Harvard could dramatically increase the efficacy of treatment.

In addition to disabling a tumor’s defenses and delivering anti-cancer drugs, the new nanodevice fluoresces can help scientists monitor treatment.

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In the war against cancer, scientists often have to act like battlefield commanders, devising creative attack strategies to bring the disease to its knees. A new tactic developed by researchers from MIT, Harvard Medical school and Queen Mary University of London involves a super-small device that disarms cancer cells so tumor-shrinking drugs can be delivered.

The device, known as a “nanobeacon,” consists of a gold nanoparticle covered with strands of DNA. Before the nanobeacon is activated inside a cell, the DNA strands are folded back on themselves like hairpins. When they arrive at the right spot inside a cancer cell, however, the strands open up, releasing anti-cancer drugs and binding to messenger RNA (mRNA), “the snippet of genetic material that carries DNA’s instructions to the rest of the cell,” according to an MIT news report about the research published Monday in Proceedings of the National Academy of Sciences.

Specifically, the nanobeacons latch onto the strand of mRNA responsible for making a protein known as MRP-1. When overexpressed, this protein, found in all cancer cells to varying degrees, can act like a pump that eliminates treatment drugs, rendering them ineffective. When the nanobeacons connect with the RNA, however, this mechanism is disabled. In effect, the drug-resistant gene inside the cancer cell is shut down cold.

Additionally, Artzi adds that the nanobeacons can be engineered to interact with other genes inside cancer cells — not just those responsible for producing drug-resistance proteins. In fact, the researchers are now experimenting with using the method to shut down a gene that causes gastric tumors to spread to the lungs.

Immune ‘Hotspots’ Associated with Better Survival in New Breast Cancer Test

A new study show that scientists develop a new test which can predict the survival chances of women with breast cancer by analysing images of ‘hotspots’ where there has been a fierce immune reaction to a tumour. The finding is published in the journal Modern Pathology.

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Investigators analysed tumor samples from 245 woman with a type of breast cancer called oestrogen receptor negative, via using statistical software to track the extent to which the immune system was homing in and attacking breast cancer cells.

They found that images of hotspots where immune cells were spatially clustered together around breast cancer cells provided a better measure of immune response than simply the numbers of immune cells within a tumour.

The patients were split into two groups based on the numbers of immune hotspots spots within their tumours. And researchers found that women whose cancers had a high number of spots lived an average of 91 months before their cancer spread, compared with just 64 months for those with a low number of spots.

Promise of Diagnostic Test

The test, described in the paper, become the first objective method of measuring the strength of a patient’s immune response to their tumour. Its automated analysis could complement existing methods where pathologists examine tumour samples under the microscope to gain a sense of whether there is a strong immune response.

The research aims to develop completely new ways of distinguishing more and less aggressive cancers, based on how successful the immune system is in keeping tumours in check. It is required to assess how many immune cells there are, but whether these are clustered together into cancer-busting hotspots, therefore mesuring the strength of an immune response to a cancer.

By analysing the complex ways in which the immune system interacts with cancer cells, investigators can split women with breast cancer into two groups, who might need different types of treatment, such as immunotherapy. The study has found an ingenious approach to generate and understand data from images of biopsy samples, which are already taken from patients but not analysed in a mathematical way.

Reference:

Beyond immune density: critical role of spatial heterogeneity in estrogen receptor-negative breast cancer. Modern Pathology, 2015; DOI: 10.1038/modpathol.2015.37

Breast cancer immunobiology driving immunotherapy: vaccines and immune checkpoint blockade

Breast cancer is immunogenic, and infiltrating immune cells in primary breast tumors convey important clinical prognostic and predictive information. Furthermore, the immune system is critically involved in clinical responses to some standard cancer therapies.

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Early breast cancer vaccine trials have established the safety and bioactivity of breast cancer immunotherapy, with hints of clinical activity. Novel strategies for modulating regulators of immunity, including regulatory T cells, myeloid-derived suppressor cells and immune checkpoint pathways (monoclonal antibodies specific for the cytotoxic T-lymphocyte antigen-4 or programmed death), are now available. In particular, immune checkpoint blockade has enormous therapeutic potential. Integrative breast cancer immunotherapies that strategically combine established breast cancer therapies with breast cancer vaccines, immune checkpoint blockade or both should result in durable clinical responses and increased cures.

Reference:

Leisha A Emens. Breast cancer immunobiology driving immunotherapy: vaccines and immune checkpoint blockade [J].NIH Public Access.

New Resistance Gene of Testicular Germ Cell Tumors Identified

A new research recently has discovered some key gene mutations that drive testicular germ cell tumors(TGCTs), and identified the key resistance genes which cause this cancer. It is the first time to apply the latest gene sequencing technology to look for the related details of TGCTs which is the most common cancer in young male. This study was published in Nature Communications.

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Testicular germ cell tumors are the most common cancer affecting young men, with a mean age at diagnosis of 36 years. The main TGCT histologies are seminomas, which resemble undifferentiated primary germ cells, and non-seminomas, which show differing degrees of differentiation.

Overall, TGCTs are markedly aneuploid with recurring gain of chromosomes 7, 8, 21, 22 and X. In addition, gain of chromosomal material from 12p is noted in virtually all cases, with genomic amplification and overexpression of genes in the 12p11.2-p12.1 region reported in ~10% of TGCTs.

In this study , scientists perform whole-exome sequencing(WES) of 42 TGCTs to comprehensively study the cancer’s mutational profile. The mutation rate is uniformly low in all of the rumors as compared with common cancers, consistent with the embryological origin of TGCT. In addition to expected copy number gain of chromosome 12p and mutation of KIT, they identify recurrent mutations in the tumour suppressor gene CDC27. Copy number analysis reveals recurring amplification of the spermatocyte development gene FSIP2 and a 0.4 Mb region at Xq28.

Their findings provide further insights into genes involved in the development and progression of TGCT.

Cancer related signaling pathway, e.g. Wnt signaling,stat3,NF-KB