p53 Isoform Promotes Cancer Stem Cell Potential

Scientists from France have identified a TP53 spliceosome which could positively regulate SOX2, OCT3/4 , NANOG, and other pluripotency key factors that promote cancer stem cell’s pluripotency. Then, it could increase the risk of cancer recurrence. The study was published in Stem Cell Report.


The p53 functions are ubiquitously altered in cancer cells by mutations/perturbation of its signaling pathways, and loss of p53 activity is a prerequisite for cancer development. Many reports have documented a p53 role in stem cell homeostasis and pluripotency. Wild-type (WT) p53 counteracts somatic cell reprogramming, whereas mutant p53 stimulates induced pluripotent stem (iPS) cell formation.

The p53 isoforms modify p53 transcriptional activity in many processes, such as cell-cycle progression, programmed cell death, replicative senescence, cell differentiation, vial replication, and angiogenesis. p53 isoforms are specifically deregulated in human tumors. However, the functions of p53 isoforms in cancer stem cell(CSC) homeostasis have never been explored.

In this study, researchers show that Δ133p53β isoform is specifically involved in promoting cancer cells stemness. Overexpression of Δ133p53β in human breast cancer cell lines stimulated mammosphere formation and the expression of key pluripotency and stemness regulators, but nor C-MYC. Furthermore, using MDA-MB-231-based cell lines, they show that increased expression of Δ133p53 isoforms correlates with the increased metastatic potential and with mammosphere formation. Finally, incubation of MCF-7 and MDA-MB-231 cells with the anti-cancer drug etoposide also promoted cell stemness in aΔ133p53-dependent manner.

Their results demonstrate that short p53 isoforms positively regulate CSC potential regardless of any p53 mutation. Consequently, WT TP53, which is considered a tumor suppressor gene, also can act as an oncogene through Δ133p53 expression.


Arsic N, Gadea G, Lagerqvist E L, et al. The p53 Isoform Δ133p53β Promotes Cancer Stem Cell Potential[J]. Stem Cell Reports, 2015.

New Mechanism of ERK in Accelerating Pancreatic Cancer Development Identified

Scientists from Fudan University Medical School have discovered that phosphokinase ERK could accelerate the degradation of FBW7 by phosphorylation. This process influences the function of FBW7 as tumor-inhibiting factor, then accelerate pancreatic cancer development. This study was published in Cell Research.


Pancreatic ductal adenocarcinoma(PDAC), the most common form of pancreatic cancer, is a devastating disease with a 5-year overall survival rate of < 5%, the highest fatality rate among all cancers. The incidence of pancreatic cancer remains equal to its mortality rate.

F-box and WD repeat domain-containing 7 (FBW7) is the substrate recognition component of the Skp1-Cull-F-box(SCF) ubiquitin ligase complex and functions as a major tumor suppressor by targeting various oncoproteins for degradation. Genomic deletion or mutation of FBW7 has frequently been identified in many human cancers but not in PDAC. Thus, it is important to know how the tumor suppressive function of FBW7 is impaired in pancreatic cancer.

In this study, researchers report that FBW7 is rarely mutated and the protein level is significantly downregulated in PDAC, through a mechanism involving an activated Ras-Raf-MEK-ERK signaling pathway. They demonstrate that ERK kinase directly interacts with and phosphorylates FBW7 at Thr205, which leads

Through the study, scientists established a novel link between the oncogenic KRAS-mutant/MAPK/ERK signaling axis and the tumor suppressor FBW7 and revealed the mechanism underlying the impairment of FBW7 function in PDAC. These findings may help develop new therapeutic strategies to treat pancreatic cancer.


Ji S, Qin Y, Shi S, et al. ERK kinase phosphorylates and destabilizes the tumor suppressor FBW7 in pancreatic cancer[J]. Cell research, 2015.

Decline in smoking rates could increase deaths from lung cancer

More people may die from undiagnosed lung cancer because they don’t qualify for low-dose CT scans, according to a study by Mayo Clinic researchers. The researchers blame current screening guidelines that have remained the same despite the decline in smoking rates in the U.S.


“Our data raise questions about the current recommendations,” said Mayo pulmonologist, Dr. David E. Midthun, one of the study authors. “We do not have the best tool to identify who is at risk for lung cancer.”

Over the study period the percentage of lung cancer patients who would have been eligible for CT screening under current guidelines fell dramatically: from 56.8% in 1984-1990 to 43.3% in 2005-2011. The proportion of men who would have been eligible decreased from 60% to 49.7%, while the percentage of women dropped from 52.3% to 36.6%.

Researchers worry about the trend. “We don’t want to disincentive patients to stop smoking,” Midthun told CNN in a phone interview. “When I told one of my patients about the study, his first question was, ‘If I stop smoking will I have to stop screening?’”

“We want people to stop smoking, and we don’t want them to lie or continue smoking just so they can be screened,” added Midthun. “We need better tools to make risk calculations for those who should be screened.” “There’s nothing magical in 30-year pack history,” added Midthun. He told CNN that age is an equally important factor. “For example, if a person stops smoking at age 55, his risk of lung cancer at age 70 is higher than it was at age 55 when he quit.”

The study was published in the February 24, 2015 issue of JAMA, the journal of the American Medical Association. It was funded by the Mayo Clinic and grants from the National Institutes of Health and the National Institute on Aging.


Vegetarians who eat fish could be greatly reducing their risk of colon cancer

Dropping red meat, and sticking to a plant-based diet that incorporates fish may be the key to preventing colorectal (colon and rectum) cancers, according to a seven-year study published Monday. Pescetarians, as they are commonly referred, had a 43% lower chance of getting the cancer compared to people with omnivorous diets.


Why focus on colorectal cancer? It is the third most diagnosed cancer, and the third leading cause of cancer-related death in the US in 2014, according to American Cancer Society statistics. The disease is particularly dangerous because it is usually asymptomatic in its early stages, making it more difficult to detect when it’s less deadly. Only 59% of those recommended for screenings receive procedures that are in line with the American Cancer Society’s standards.

The study, which followed nearly 78,000 people and was published in the Journal of American Medical Association, adds to the growing body of evidence touting the health benefits of a plant-based diet. Another study, reviewing data from 39 separate studies showing that a plant based diet leads to an average drop in blood pressure similar to 30-60 minutes of exercise per day.

Nutritionist Lisa Drayer agrees. “In addition to other dietary factors, fish may provide added protection from its high content omega-3 fatty acids. This is consistent with previous research that has found omega-3s have anti-cancer activity and that they may be helpful in the prevention and treatment of colorectal cancer.”

But despite the caveat, Drayer is optimistic. “While the study is observational and cannot prove a cause/effect relationship, it is exciting to think that in addition to regular screenings, a diet rich in fish and fiber-rich foods may play an important role in reducing the risk of colorectal cancer.”

Vismodegib Resistance in Basal Cell Carcinoma: Not a Smooth Fit

In 2010, an estimated 2.8 million cases of BCC were diagnosed in the US, and the figures have continued to climb. In fact, BCC is the most frequently occurring form of all cancers. More than one out of every three new cancers is a skin cancer, and the vast majority are BCCs.

BBC can be result in the activation of Hedgehog(HH) mutations and HH by binding with Patched (PTCH) play a role. PTCH inhabit activation of its downstream heptahelical transmembrane protein smoothened(SMO) to active the activation of Gli transcription factor. Ultimately, HH gene expressed.

In 1987, cyclopamine was proved to be inhibitor of HH signaling pathway. 13 years later, SMO was approved subsequently. Researches show that the resistance of BBC to SMO is resource from SMO mutation which also confers vismodegib resistance. What is more, mutation outside of ligand binding pocket could promote activity of SMO even without inhibitors. On the other side, mutation of binding pocket had little effect on basal SMO activity.

The activation of SMO which is downstream of HH signaling can result in any resistance of SMO-targeted inhibitor. So, the ideal therapies may contain drug combination which also targets Gli.

New Target in the Treatment of Pancreatic Cancer

Pancreatic cancer is considered largely incurable, even when diagnosed at an early stage. Due to a lack of early symptoms and the aggressive nature of pancreatic tumors, pancreatic cancer patients are often diagnosed at late stage, when metastasis has already occurred. The poor prognosis of pancreatic cancer has been mainly attributed to its aggressive local invasion and early metastasis.


Researchers from Taiwan have discovered that overexpression of IL-17B receptor(IL-17RB) strongly correlated with postoperative metastasis and inversely correlated with progression-free survival in pancreatic cancer patients. Their study was published in JEM.

IL-17RB has been detected in kidney, pancreas, liver, brain, and intestine, and up-regulation of IL-17RB expression was found in intestinal inflammation. Overexpression was associated with poor breast cancer prognosis. Depletion of IL-17RB resulted in reduction of tumorigenic ability of breast cancer cells. It is likely that IL-17B-IL-17RB autocrine signaling may contribute to the malignant nature of pancreatic cancer.

In this study, researchers found that IL-17B/RB signaling is essential for pancreatic cancer malignancy. IL-17B-IL-17RB signal pathway enhanced tumor malignancy through two distinct pathways. One was to activate IL-8 expression via transcription factors nuclear factor κB(NF- κB) and activator protein-1 (AP-1) to promote incasion and vasculogenic endothelial cell recruitment. Importantly, treatment with a newly developed monoclonal antibody against IL-17RB blocked tumor growth and metastasis, and also promoted survival in a mouse xenograft model.

These findings shed light on the underlying mechanism of pancreatic cancer malignancy and provide a promising therapeutic target to inhibit pancreatic cancer progression.


 Wu H H, Hwang-Verslues W W, Lee W H, et al. Targeting IL-17B–IL-17RB signaling with an anti–IL-17RB antibody blocks pancreatic cancer metastasis by silencing multiple chemokines[J]. The Journal of experimental medicine, 2015, 212(3): 333-349.

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.


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.


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



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.


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.


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.


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.


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.