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hallmarks_of_cancer

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501

22851646_6

Chaos3 mammary tumor cells exhibit RAS hyperactivation and increased sensitivity to RAS pathway inhibitors .

502

22851646_7

These results indicate that spontaneous NF1 loss can drive breast cancer .

503

22851646_8

This should be informative for treatment of the significant fraction of patients whose tumors bear NF1 mutations .

504

23197380_0

Prohibiting angiogenesis is an important therapeutic approach for fighting cancer and other angiogenic related diseases .

505

23197380_1

Research focused on proteins that regulate abnormal angiogenesis has attracted intense interest in both academia and industry .

506

23197380_2

Such proteins are able to target several angiogenic factors concurrently , thereby increasing the possibility of therapeutic success .

507

23197380_3

Aquaporin-1 ( AQP1 ) is a water channel membrane protein that promotes tumour angiogenesis by allowing faster endothelial cell migration .

508

23197380_4

In this study we test the hypothesis that AQP1 inhibition impairs tumour growth in a mouse model of melanoma .

509

23197380_5

After validating the inhibitor efficacy of two different AQP1 specific siRNAs in cell cultures , RNA interference experiments were performed by intratumoural injections of AQP1 siRNAs in mice .

510

23197380_6

After 6 days of treatment , AQP1 siRNA treated tumours showed a 75 % reduction in volume when compared to controls .

511

23197380_7

AQP1 protein level , in AQP1 knockdown tumours , was around 75 % that of the controls and was associated with a significant 40 % reduced expression of the endothelial marker , Factor VIII .

512

23197380_8

Immunofluorescence analysis of AQP1 siRNA treated tumours showed a significantly lower microvessel density .

513

23197380_9

Time course experiments demonstrated that repeated injections of AQP1 siRNA over time are effective in sustaining the inhibition of tumour growth .

514

23197380_10

Finally , we have confirmed the role of AQP1 in sustaining an active endothelium during angiogenesis and we have shown that AQP1 reduction causes an increase in VEGF levels .

515

23197380_11

In conclusion , this study validates AQP1 as a pro-angiogenic protein , relevant for the therapy of cancer and other angiogenic-related diseases such as psoriasis , endometriosis , arthritis and atherosclerosis .

516

22829774_0

The Alternative Lengthening of Telomeres ( ALT ) pathway is a telomerase-independent pathway for telomere maintenance that is active in a significant subset of human cancers and in vitro immortalized cell lines .

517

22829774_1

ALT is thought to involve templated extension of telomeres through homologous recombination , but the genetic or epigenetic changes that unleash ALT are not known .

518

22829774_2

Recently , mutations in the ATRX/DAXX chromatin remodeling complex and histone H3.3 were found to correlate with features of ALT in pancreatic neuroendocrine cancers , pediatric glioblastomas , and other tumors of the central nervous system , suggesting that these mutations might contribute to the activation of the ALT pathway in these cancers .

519

22829774_3

We have taken a comprehensive approach to deciphering ALT by applying genomic , molecular biological , and cell biological approaches to a panel of 22 ALT cell lines , including cell lines derived in vitro .

520

22829774_4

Here we show that loss of ATRX protein and mutations in the ATRX gene are hallmarks of ALT-immortalized cell lines .

521

22829774_5

In addition , ALT is associated with extensive genome rearrangements , marked micronucleation , defects in the G2/M checkpoint , and altered double-strand break ( DSB ) repair .

522

22829774_6

These attributes will facilitate the diagnosis and treatment of ALT positive human cancers .

523

21044925_0

BACKGROUND AND AIMS breast reconstruction with silicone prosthesis following nipple-sparing mastectomy has become widely accepted as a reconstruction option in women requiring mastectomy for cancer .

524

21044925_1

The purpose of this study was to evaluate the incidence and some factors influencing early local complications in patients undergoing NSM with immediate implant reconstruction .

525

21044925_2

MATERIAL AND METHODS prospective study was performed on a consecutive series of 214 breast reconstructions in 205 patients .

526

21044925_3

All complications during the six weeks after surgery were recorded. 42 prostheses were implanted after neoadjuvant chemotherapy , 27 patients previously had radiotherapy due to breast conserving surgery and in all other cases surgery was the pri-mary treatment for cancer .

527

21044925_4

RESULTS the overall six-week complication rate was 16% ( 35 ) and included : major skin flap necrosis ( 4% , 9 procedures ) , minor skin necrosis ( 3% , 7 ) , major infection ( 2% , 5 ) , minor infection ( 3% , 7 ) , prolonged seroma formation ( 3% , 6 ) , haematoma ( 1% , 2 ) and epidermolysis ( 1% , 2 ) .

528

21044925_5

In 6% ( 12 ) reconstruction procedures explantation of prosthesis was done .

529

21044925_6

Neoadjuvant chemo-therapy and radiotherapy were not associated with higher rate of complications .

530

21044925_7

CONCLUSION nipple-sparing mastectomy with immediate implant reconstruction has acceptable morbidity rate in the hand of experienced oncoplastic surgeon and therefore should be considered as treatment option to women requiring mastectomy .

531

22825251_0

Exposure of cells to UV light from the sun causes the formation of pyrimidine dimers in DNA that have the potential to lead to mutation and cancer .

532

22825251_1

In humans , pyrimidine dimers are removed from the genome in the form of nt-long oligomers by concerted dual incisions .

533

22825251_2

Though nearly 50 y of excision repair research has uncovered many details of UV photoproduct damage recognition and removal , the fate of the excised oligonucleotides and , in particular , the ultimate fate of the chemically very stable pyrimidine dimers remain unknown .

534

22825251_3

Physiologically relevant UV doses introduce hundreds of thousands of pyrimidine dimers in diploid human cells , which are excised from the genome within h .

535

22825251_4

Once removed from the genome , " where do all the dimers go? "

536

22825251_5

In a recent study we addressed this question .

537

22825251_6

Although our study did not determine the fate of the dimer itself , it revealed that the excised is released from the duplex in a tight complex with the transcription/repair factor TFIIH .

538

22825251_7

This finding combined with recent reports that base and oligonucleotide products of the base and double-strand break repair pathways also make stable complexes with the cognate repair enzymes , and that these complexes activate the MAP kinase and checkpoint signaling pathways , respectively , raises the possibility that TFIIH-30-mer excision complexes may play a role in signaling reactions in response to UV damage .

539

22395432_0

We have recently proposed a new two-compartment model for understanding the Warburg effect in tumor metabolism .

540

22395432_1

In this model , glycolytic stromal cells produce mitochondrial fuels ( L-lactate and ketone bodies ) that are then transferred to oxidative epithelial cancer cells , driving OXPHOS and mitochondrial metabolism .

541

22395432_2

Thus , stromal catabolism fuels anabolic tumor growth via energy transfer .

542

22395432_3

We have termed this new cancer paradigm the " reverse Warburg effect, " because stromal cells undergo aerobic glycolysis , rather than tumor cells .

543

22395432_4

To assess whether this mechanism also applies during cancer cell metastasis , we analyzed the bioenergetic status of breast cancer lymph node metastases , by employing a series of metabolic protein markers .

544

22395432_5

For this purpose , we used MCT4 to identify glycolytic cells .

545

22395432_6

Similarly , we used TO MM20 and COX staining as markers of mitochondrial mass and OXPHOS activity , respectively .

546

22395432_7

Consistent with the " reverse Warburg effect, " our results indicate that metastatic breast cancer cells amplify oxidative mitochondrial metabolism ( OXPHOS ) and that adjacent stromal cells are glycolytic and lack detectable mitochondria .

547

22395432_8

Glycolytic stromal cells included cancer-associated fibroblasts , adipocytes and inflammatory cells .

548

22395432_9

Double labeling experiments with glycolytic ( MCT4 ) and oxidative ( TO MM20 or COX ) markers directly shows that at least two different metabolic compartments co-exist , side-by-side , within primary tumors and their metastases .

549

22395432_10

Since cancer-associated immune cells appeared glycolytic , this observation may also explain how inflammation literally " fuels " tumor progression and metastatic dissemination , by " feeding " mitochondrial metabolism in cancer cells .

550

22395432_11

Finally , MCT4(+) and TO MM20(-) " glycolytic " cancer cells were rarely observed , indicating that the conventional " Warburg effect " does not frequently occur in cancer-positive lymph node metastases .

551

22189713_0

A distinct group of breast cancers , called " basal " or " triple-negative " ( TN ) cancers express both basal cytokeratins and the epidermal growth factor receptor , but fail to express estrogen receptors , progesterone receptors or HER2 and have stem-like or mesenchymal features .

552

22189713_1

They are particularly aggressive , are frequently chemo-resistant , with p53 mutation , up-regulation of IL-6 and Stat3 .

553

22189713_2

Because TN cells are particularly sensitive to the anti-diabetic agent metformin , we hypothesized that it may target JAK2/Stat3 signaling .

554

22189713_3

The effects of metformin upon Stat3 expression and activation were examined in four human TN cell lines .

555

22189713_4

Metformin's effects were also studied in sublines with forced over-expression of constitutively active ( CA ) Stat3 , as well as lines with stable knockdown of Stat3 .

556

22189713_5

Metformin inhibited Stat3 activation ( P-Stat3 ) at Tyr705 and Ser727 and downstream signaling in each of the four parental cell lines .

557

22189713_6

CA-Stat3 transfection attenuated , whereas Stat3 knockdown enhanced , the effects of metformin upon growth inhibition and apoptosis induction .

558

22189713_7

A Stat3 specific inhibitor acted synergistically with metformin in reducing cell growth and inducing apoptosis .

559

22189713_8

An mTOR inhibitor showed no significant interaction with metformin .

560

22189713_9

In summary , Stat3 is a critical regulator of metformin action in TN cancer cells , providing the potential for enhancing metformin's efficacy in the clinical setting .

561

20632815_0

AIMS Currently , testing for mismatch repair deficiency in colorectal cancers is initiated by performing immunohistochemistry with four antibodies ( MLH1 , PMS2 , MSH2 and MSH6 ) .

562

20632815_1

If any one of these stains is negative the tumour is considered microsatellite unstable and , if clinical circumstances warrant it , the patient is offered genetic testing for Lynch's syndrome .

563

20632815_2

Due to the binding properties of the mismatch repair heterodimer complexes , gene mutation and loss of MLH1 and MSH2 invariably result in the degradation of PMS2 and MSH6 , respectively , but the converse is not true .

564

20632815_3

We propose that staining for PMS2 and MSH6 alone will be sufficient to detect all cases of mismatch repair deficiency and should replace routine screening with all four antibodies .

565

20632815_4

METHODS The electronic database of the department of Anatomical Pathology , Royal North Shore Hospital , Sydney , Australia , was searched for all colorectal carcinomas on which a four panel immunohistochemical microsatellite instability screen was performed .

566

20632815_5

An audit of the slides for concordant loss of MLH1-PMS2 and MSH2-MSH6 was then undertaken .

567

20632815_6

Unusual or discordant cases were reviewed and , in some cases , re-stained to confirm the staining pattern .

568

20632815_7

RESULTS Of 344 cases of colorectal cancer which underwent four antibody immunohistochemistry , 104 displayed loss of at least one mismatch repair protein .

569

20632815_8

Of these , 100 showed concordant mismatch repair loss ( i.e. , loss of MLH1 and PMS2 or loss of MSH2 and MSH6 ) .

570

20632815_9

The four discordant cases comprised two single negative cases ( 1 MSH6 negative/MSH2 positive case , 1 PMS2 negative/MLH1 positive ) and two triple negative ( both MLH1/PMS2/MSH6 negative ) .

571

20632815_10

The microsatellite instability ( MSI ) group showed a relatively high median age ( 69.3 years ) due to the departmental policy of testing all cases with possible MSI morphology regardless of age .

572

20632815_11

CONCLUSIONS The sensitivity and specificity of a two panel test comprised of PMS2 and MSH6 , compared to a four panel test , is 100% .

573

20632815_12

No false negatives or positives were identified .

574

20632815_13

We conclude that the two panel test should replace a four panel protocol for immunohistochemical screening for mismatch repair deficiency .

575

1371284_0

Lipoprotein lipase ( LPL ) plays a central role in normal lipid metabolism as the key enzyme involved in the hydrolysis of triglycerides present in chylomicrons and very low density lipoproteins .

576

1371284_1

LPL is a member of a family of hydrolytic enzymes that include hepatic lipase and pancreatic lipase .

577

1371284_2

Based on primary sequence homology of LPL to pancreatic lipase , Ser-132 , Asp-156 , and His-241 have been proposed to be part of a domain required for normal enzymic activity .

578

1371284_3

We have analyzed the role of these potential catalytic residues by site-directed mutagenesis and expression of the mutant LPL in human embryonic kidney-293 cells .

579

1371284_4

Substitution of Ser-132 , Asp-156 , and His-241 by several different residues resulted in the expression of an enzyme that lacked both triolein and tributyrin esterase activities .

580

1371284_5

Mutation of other conserved residues , including Ser-97 , Ser-307 , Asp-78 , Asp-371 , Asp-440 , His-93 , and His-439 resulted in the expression of active enzymes .

581

1371284_6

Despite their effect on LPL activity , substitutions of Ser-132 , Asp-156 , and His-241 did not change either the heparin affinity or lipid binding properties of the mutant LPL .

582

1371284_7

In summary , mutation of Ser-132 , Asp-156 , and His-241 specifically abolishes total hydrolytic activity without disrupting other important functional domains of LPL .

583

1371284_8

These combined results strongly support the conclusion that Ser-132 , Asp-156 , and His-241 form the catalytic triad of LPL and are essential for LPL hydrolytic activity .

584

22835516_0

A 34-year-old Japanese woman presented with left supraclavicular lymph node swelling .

585

22835516_1

Computed tomography scans revealed a mass on the left lower lobe , pulmonary nodules , and pleural effusion .

586

22835516_2

A lymph node biopsy revealed large-cell carcinoma with an epidermal growth factor receptor ( EGFR ) deletion mutation , L747-T751 in exon 19 .

587

22835516_3

Although malignant pleural effusions carried the same EGFR mutation , progressive pleural effusions after treatment with chemotherapy , gefitinib , and erlotinib did not show any EGFR mutation .

588

22835516_4

A cell line established from the pleural effusion 3 days before the patient expired also did not harbor the EGFR mutation .

589

22835516_5

Histological sections of the lymph node of the patient were similar to those of the xenograft tumor of the cell line .

590

22835516_6

There may be genetic heterogeneity in EGFR mutant tumors .

591

21975289_0

BACKGROUND Hepatocellular carcinoma ( HCC ) is the most common liver cancer .

592

21975289_1

Therapeutic results are usually unsatisfactory because liver tumors recur often .

593

21975289_2

Immunologic factors may be related to the recurrence of HCC ; however , this possibility is mentioned only rarely .

594

21975289_3

METHODS Thirty HCC patients undergoing hepatectomies were divided into 3 groups according to the diameters of their HCCs : group A ( n = 8 ) , diameter ≤3 cm ; group B ( n = 8 ) , diameter >3 cm and ≤5 cm ; and group C ( n = 14 ) , diameter >5 cm .

595

21975289_4

T-lymphocytes from peripheral blood , nontumor liver tissue , and the HCC were analyzed .

596

21975289_5

RESULTS The percentage of CD25+ in the CD4+ T cells did not differ between the peripheral blood and the nontumor liver tissue among the 3 groups .

597

21975289_6

CD25+ cells were increased in the tumor tissue in group C patients ( range , 6-41% ; median , 22.9% ; P = .003 ) , compared to group A patients .

598

21975289_7

The percentage of CD25+ in the CD4+ T cells in tumor tissue was positively correlated with tumor sizes ( r = 0.556 ) .

599

21975289_8

These CD4+ CD25+ lymphocytes produced transforming growth factor-β and interferon-γ but not interleukin-10 , and were anergic to plate-coated monoclonal antibodies ( anti-CD3/anti-CD28 ) .

600

21975289_9

The characteristics of these antibodies were comparable to those of regulatory T cells .