#Cancer Cell

‘Promising Times’ for Patients With CLL

A fixed-duration treatment regimen may result in better outcomes and less time in the hospital for patients with CLL. A fixed-duration treatment regimen of Imbruvica (ibrutinib) and Venclexta (venetoclax) may lead to better progression-free survival, as well as less time spent in the hospital, for patients with chronic lymphocytic leukemia (CLL).
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Candy Crush: Could Blue M&M’s Repair Spinal Cord Injuries?

The same chemical in the food dye keeps damaged nerves alive. They melt in your mouth, not in your hands. But could M&M’s — in particular the blue ones — hold the key to healing the irreversible damage caused by spinal cord injuries?. One of the Ms in their name...
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Lauren Albrecht Joins UC Irvine as an Assistant Professor

The UC Irvine School of Pharmacy & Pharmaceutical Sciences has announced Lauren Albrecht, PhD, as an assistant professor for pharmaceutical sciences, effective October 1. “We are pleased to welcome Lauren to our growing department,” said Richard Chamberlin, PhD, Professor and Chair of the Department of Pharmaceutical Sciences. “Her exciting research on cancer metabolism complements that of other PharmSci faculty who are studying other aspects of cancer cell biology. Lauren’s work also aligns with a number of groups in the department that are developing methods for translating that information at the cellular level into new approaches for cancer prevention, treatment, or diagnosis.”
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NeuroD1 promotes tumor cell proliferation and tumorigenesis by directly activating the pentose phosphate pathway in colorectal carcinoma

Tumor metabolic reprogramming ensures that cancerous cells obtain sufficient building blocks, energy, and antioxidants to sustain rapid growth and for coping with oxidative stress. Neurogenic differentiation factor 1 (NeuroD1) is upregulated in various types of tumors; however, its involvement in tumor cell metabolic reprogramming remains unclear. In this study, we report that NeuroD1 is positively correlated with glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme in the pentose phosphate pathway (PPP), in colorectal cancer cells. In addition, the regulation of G6PD by NeuroD1 alters tumor cell metabolism by stimulating the PPP, leading to enhanced production of nucleotides and NADPH. These, in turn, promote DNA and lipid biosynthesis in tumor cells, while decreasing intracellular levels of reactive oxygen species. Mechanistically, we showed that NeuroD1 binds directly to the G6PD promoter to activate G6PD transcription. Consequently, tumor cell proliferation and colony formation are enhanced, leading to increased tumorigenic potential in vitro and in vivo. These findings reveal a novel function of NeuroD1 as a regulator of G6PD, whereby its oncogenic activity is linked to tumor cell metabolic reprogramming and regulation of the PPP. Furthermore, NeuroD1 represents a potential target for metabolism-based anti-tumor therapeutic strategies.

MCPIP1 inhibits Wnt/β-catenin signaling pathway activity and modulates epithelial-mesenchymal transition during clear cell renal cell carcinoma progression by targeting miRNAs

Epithelial-mesenchymal transition (EMT) refers to the acquisition of mesenchymal properties in cells participating in tumor progression. One hallmark of EMT is the increased level of active β-catenin, which can trigger the transcription of Wnt-specific genes responsible for the control of cell fate. We investigated how Monocyte Chemotactic Protein-1-Induced Protein-1 (MCPIP1), a negative regulator of inflammatory processes, affects EMT in a clear cell renal cell carcinoma (ccRCC) cell line, patient tumor tissues and a xenotransplant model. We showed that MCPIP1 degrades miRNAs via its RNase activity and thus protects the mRNA transcripts of negative regulators of the Wnt/β-catenin pathway from degradation, which in turn prevents EMT. Mechanistically, the loss of MCPIP1 RNase activity led to the upregulation of miRNA-519a-3p, miRNA-519b-3p, and miRNA-520c-3p, which inhibited the expression of Wnt pathway inhibitors (SFRP4, KREMEN1, CXXC4, CSNK1A1 and ZNFR3). Thus, the level of active nuclear β-catenin was increased, leading to increased levels of EMT inducers (SNAI1, SNAI2, ZEB1 and TWIST) and, consequently, decreased expression of E-cadherin, increased expression of mesenchymal markers, and acquisition of the mesenchymal phenotype. This study revealed that MCPIP1 may act as a tumor suppressor that prevents EMT by stabilizing Wnt inhibitors and decreasing the levels of active β-catenin and EMT inducers.

Investigating Why Small Cell Lung Cancer Is So Aggressive

Imagine you’re about to go on a cross-country trip, stopping at spots along the way to admire local attractions. You’d probably want to have road atlas handy, containing maps at different scales, covering both the major highways and the roads of smaller cities and towns — or at least a GPS that can access a digital atlas with this information.

New atlas of small cell lung cancer reveals rare population of stem-like cells with metastatic properties

Imagine you're about to go on a cross-country trip, stopping at spots along the way to admire local attractions. You'd probably want to have road atlas handy, containing maps at different scales, covering both the major highways and the roads of smaller cities and towns -; or at least a GPS that can access a digital atlas with this information.

VIDEO: Antibody-drug conjugate ‘encouraging' in lung cancer subsets

In an interview with Healio, Pasi A. Jänne, MD, PhD, discussed a study on the use of an antibody-drug conjugate in some patients with non-small cell lung cancer. Jänne, director of the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School, explained that phase 1 trial results presented at the meeting from a study assessing the TROP2 antibody-drug conjugate DS-1062a found that there was some response to treatment among patients with advanced or metastatic NSCLC who had actionable genomic.

A positive feedback loop of lncRNA-RMRP/ZNRF3 axis and Wnt/β-catenin signaling regulates the progression and temozolomide resistance in glioma

Drug resistance strikingly limits the therapeutic effect of temozolomide (TMZ) (a common drug for glioma). Long non-coding RNA (lncRNA) RMRP has been found to be implicated in glioma progression. However, the effect of RMRP on TMZ resistance along with related molecular mechanisms is poorly defined in glioma. In the present study, RMRP, ZNRF3, and IGF2BP3 were screened out by bioinformatics analysis. The expression levels of lncRNAs and mRNAs were measured by RT-qPCR assay. Protein levels of genes were detected by western blot and immunofluorescence assays. ZNRF3 mRNA stability was analyzed using Actinomycin D assay. Cell proliferative ability and survival rate were determined by CCK-8 assay. Cell apoptotic pattern was estimated by flow cytometry. The effect of RMRP knockdown on the growth of TMZ-treated glioma xenograft tumors was explored in vivo. The relationships of IGF2BP3, RMRP, and ZNRF3 were explored by bioinformatics prediction analysis, RNA immunoprecipitation, luciferase, and RNA pull-down, and chromatin immunoprecipitation assays. The results showed that RMRP was highly expressed in glioma. RMRP knockdown curbed cell proliferation, facilitated cell apoptosis and reduced TMZ resistance in glioma cells, and hindered the growth of TMZ-treated glioma xenograft tumors. RMRP exerted its functions by down-regulating ZNRF3 in glioma cells. IGF2BP3 interacted with RMRP and ZNRF3 mRNA. IGF2BP3 knockdown weakened the interaction of Argonaute 2 (Ago2) and ZNRF3. RMRP reduced ZNRF3 expression and mRNA stability by IGF2BP3. RMRP knockdown inhibited β-catenin expression by up-regulating ZNRF3. The inhibition of Wnt/β-catenin signaling pathway by XAV-939 weakened RMRP-mediated TMZ resistance in glioma cells. β-catenin promoted RMRP expression by TCF4 in glioma cells. In conclusion, RMRP/ZNRF3 axis and Wnt/β-catenin signaling formed a positive feedback loop to regulate TMZ resistance in glioma. The sustained activation of Wnt/β-catenin signaling by RMRP might contribute to the better management of cancers.

New Guidelines For Basal Cell Cancer

The National Comprehensive Cancer Network (NCCN®) today announced the publication of new NCCN Guidelines for Patients® Basal Cell Skin Cancer (also known as basal cell carcinoma, or BCC), the most common form of skin cancer. This highly curable type of cancer is diagnosed in more than two million people in the United States every year—which is more than all other cancers combined.[1] BCC primarily impacts lighter-skinned, sun-exposed people over age 60, due to the buildup of sun exposure over the years. However, skin cancer has recently become more common in younger people, likely as a result of them spending more time in the sun. In very rare instances untreated BCC can progress significantly and be life-threatening. This new resource provides trustworthy information based on the latest evidence, available free online at thanks to funding from the NCCN Foundation®.

Molecular atlas of small cell lung cancer reveals unusual cell type that could explain why it's so aggressive

Imagine you're about to go on a cross-country trip, stopping at spots along the way to admire local attractions. You'd probably want to have road atlas handy, containing maps at different scales, covering both the major highways and the roads of smaller cities and towns—or at least a GPS that can access a digital atlas with this information.

Poziotinib Shows Promise in HER2 Exon 20-Mutant Non-Small Cell Lung Cancer

The tyrosine kinase inhibitor poziotinib showed “promising” antitumor activity in patients with advanced HER2 exon 20-mutant non-small cell lung cancer (NSCLC), according to researchers. They reported these results, from a phase 2 trial, in the Journal of Clinical Oncology. The single-arm study ( Identifier: NCT03066206) included 30 patients with previously...

Angiogenic effects of cell therapy within a biomaterial scaffold in a rat hind limb ischemia model

Critical limb ischemia (CLI) is a life- and limb-threatening condition affecting 1"“10% of humans worldwide with peripheral arterial disease. Cellular therapies, such as bone marrow-derived mesenchymal stem cells (MSCs) have been used for the treatment of CLI. However, little information is available regarding the angiogenic potency of MSCs and mast cells (MC) in angiogenesis. The aim of this study was to evaluate the ability of MCs and MSCs to induce angiogenesis in a rat model of ischemic hind limb injury on a background of a tissue engineered hydrogel scaffold. Thirty rats were randomly divided into six control and experimental groups as follows: (a) Control healthy (b) Ischemic positive control with right femoral artery transection, (c) ischemia with hydrogel scaffold, (d) ischemia with hydrogel plus MSC, (e) ischemia with hydrogel plus MC and (f) ischemia with hydrogel plus MSC and MCs. 106 of each cell type, isolated from bone marrow stroma, was injected into the transected artery used to induce hind limb ischemia. The other hind limb served as a non-ischemic control. After 14Â days, capillary density, vascular diameter, histomorphometry and immunohistochemistry at the transected location and in gastrocnemius muscles were evaluated. Capillary density and number of blood vessels in the region of the femoral artery transection in animals receiving MSCs and MCs was increased compared to control groups (P"‰<"‰0.05). Generally the effect of MCs and MSCs was similar although the combined MC/MSC therapy resulted in a reduced, rather than enhanced, effect. In the gastrocnemius muscle, immunohistochemical and histomorphometric observation showed a great ratio of capillaries to muscle fibers in all the cell-receiving groups (P"‰<"‰0.05). The data indicates that the combination of hydrogel and cell therapy generates a greater angiogenic potential at the ischemic site than cell therapy or hydrogels alone.

Choueiri Shares Highlights From the 2021 Kidney Cancer Research Summit

Toni Choueiri, MD, discusses key highlights from the 2021 Kidney Cancer Research Summit and exciting research efforts underway in renal cell carcinoma. The 2021 Kidney Cancer Research Summit (KCRS) brought together clinicians, researchers, patients, and kidney cancer advocates to discuss the latest updates in basic science, translational, and clinical research within the realm of kidney cancer, according to Toni Choueiri, MD, who added that for many, this was the first in-person conference since the start of the COVID-19 pandemic.

ULK1 promotes mitophagy via phosphorylation and stabilization of BNIP3

UNC51-like kinase-1 (ULK1) is the catalytic component of the autophagy pre-initiation complex that stimulates autophagy via phosphorylation of ATG14, BECLN1 and other autophagy proteins. ULK1 has also been shown to specifically promote mitophagy but the mechanistic basis of how has remained unclear. Here we show that ULK1 phosphorylates the BNIP3 mitochondrial cargo receptor on a critical serine residue (S17) adjacent to its amino terminal LIR motif. ULK1 similarly phosphorylates BNIP3L on S35. Phosphorylation of BNIP3 on S17 by ULK1 promotes interaction with LC3 and mitophagy. ULK1 interaction also promotes BNIP3 protein stability by limiting its turnover at the proteasome. The ability of ULK1 to regulate BNIP3 protein stability depends on an intact "BH3" domain and deletion of its "BH3" domain reduces BNIP3 turnover and increases BNIP3 protein levels independent of ULK1. In summary ULK1 promotes mitophagy by both stabilization of BNIP3 protein and via phosphorylation of S17 to stimulate interaction with LC3.

CHD1L augments autophagy-mediated migration of hepatocellular carcinoma through targeting ZKSCAN3

Autophagy is an important biological process in normal cells. However, how it affects tumor progression still remains poorly understood. Herein, we demonstrated that the oncogenic protein Chromodomain-helicase-DNA-binding-protein 1-like gene (CHD1L) might promote HCC cells migration and metastasis through autophagy. CHD1L could bind to the promotor region of Zinc finger with KRAB and SCAN domain 3 (ZKSCAN3), a pivotal autophagy suppressor, and inhibit its transcription. We established inducible CHD1L conditional knockout cell line (CHD1L-iKO cell) and found that the deletion of CHD1L significantly increased ZKSCAN3 expression both at mRNA and protein level. Deletion of CHD1L impaired the autophagic flux and migration of HCC cells, while specifically inhibiting ZKSCAN3 blocked these effects. Further exploration demonstrated that the enhanced tumor cell migration and metastasis induced by CHD1L was mediated through ZKSCAN3-induced autophagic degradation of Paxillin. In summary, we have characterized a previously unknown function of CHD1L in regulating tumor migration via ZKSCAN3-mediated autophagy in HCC. Further inhibition of CHD1L and its downstream autophagy signaling might shed new light on cancer therapeutics.

Prognostic impact of lingual lymph node metastasis in patients with squamous cell carcinoma of the tongue: a retrospective study

Squamous cell carcinoma (SCC) of the tongue rarely metastasizes to the lingual lymph nodes (LLNs), which are inconstant nodes and often situated outside the areas of basic tongue tumor surgery. The current study evaluated the clinicopathological features and prognostic impact of LLN metastasis (LLNM), compared to that of cervical lymph node metastasis, in patients with tongue SCC. A total of 608 patients underwent radical surgery for tongue SCC at our department between January 2001 and December 2016. During neck dissection, we scrutinized and resected lateral LLNs, when present. Of the 128 patients with lymph node metastasis, 107 had cervical lymph node metastasis and 21 had both cervical lymph node metastasis and LLNM. Univariate analysis demonstrated that LLNM was significantly associated with the adverse features of cervical lymph node metastasis. The 5-year disease-specific survival (5y-DSS) was significantly lower in patients with LLNMs than in those without LLNMs (49.0% vs. 88.4%, P"‰<"‰0.01). Moreover, Cox proportional hazards model analyses revealed that cervical lymph node metastasis at level IV or V and LLNM were independent prognostic factors for 5y-DSS. LLNM has a strong negative impact on survival in patients with tongue SCC. An advanced status of cervical lymph node metastasis may predict LLNM.

Presentation: Tipifarnib in HNSCC With HRAS Mutations

Drs Cesar Perez and Victoria Meucci Villaflor review “Tipifarnib in Head and Neck Squamous Cell Carcinoma With HRAS Mutations” by Ho AL, et al. Victoria Meucci Villaflor, MD: Hello, and welcome to Between the Lines, a Journal Club Experience. Today’s featured article is, “Tipifarnib in Head and Neck Squamous Cell Carcinoma With HRAS Mutations.” My name is Dr Victoria Villaflor. I’m the section chief of head and neck oncology and professor in the Department of Medical Oncology and Therapeutics Research at City of Hope. I’m lucky to be joined by my colleague, Dr Cesar Perez. He‘s also a head and neck medical oncologist whom I’ve known for many years. He started out in Florida and has recently moved to the Sarah Cannon Research Institute at Florida Cancer Specialists, where he’s the director of drug development. Welcome, Cesar.