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  • American Association for Cancer Research (AACR)  (31)
  • 1
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    Cathepsin B Expression and Survival in Colon Cancer: Implications for Molecular Detection of Neoplasia
    American Association for Cancer Research (AACR) ; 2010
    In:  Cancer Epidemiology, Biomarkers & Prevention Vol. 19, No. 11 ( 2010-11-01), p. 2777-2785
    Details
    In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 19, No. 11 ( 2010-11-01), p. 2777-2785
    Abstract: Background and Aims: Proteases play a critical role in tumorigenesis and are upregulated in colorectal cancer and neoplastic polyps. In animal models, cathepsin B (CTSB)–activatable imaging agents show high enzyme activity within intestinal tumors. Methods: We conducted a prospective cohort study of 558 men and women with colon cancer with tumors that were accessible for immunohistochemical assessment. We used Cox proportional hazards models, stratified by stage, to compute colon cancer–specific and overall mortality according to tumoral expression of CTSB. Results: Among 558 participants, 457 (82%) had tumors that expressed CTSB (CTSB positive) and 101 (18%) had tumors that did not express CTSB (CTSB negative). CTSB expression was not associated with disease stage (P = 0.19). After a median follow-up of 11.6 years, there were 254 total and 155 colon cancer–specific deaths. Compared with participants with CTSB-negative tumors, participants with CTSB-positive tumors experienced a multivariate hazard ratio for colon cancer–specific mortality of 1.99 (95% confidence interval, 1.19-3.34) and overall mortality of 1.71 (95% confidence interval, 1.16-2.50). CTSB expression was independently associated with KRAS (P = 0.01) and BRAF mutation (P = 0.04), but not microsatellite instability status, CpG island methylator phenotype status, PIK3CA mutation, LINE-1 methylation, TP53 expression, or PTGS2 (cyclooxygenase-2) expression. Among 123 individuals with adenomas, 91% expressed CTSB. Conclusions: As assessed by immunohistochemistry, CTSB is expressed in the vast majority of colon cancers, independent of stage, and is significantly associated with higher risk of colon cancer–specific and overall mortality. Impact: These results support the potential of CTSB a target for image detection of neoplastic lesions in humans. Cancer Epidemiol Biomarkers Prev; 19(11); 2777–85. ©2010 AACR.
    Type of Medium: Online Resource
    ISSN: 1055-9965 , 1538-7755
    URL: Article
    DOI: 10.1158/1055-9965.EPI-10-0529
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
    detail.hit.zdb_id: 2036781-8
    detail.hit.zdb_id: 1153420-5
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  • 2
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    DNA Polymerase and Mismatch Repair Exert Distinct Microsatellite Instability Signatures in Normal and Malignant Human Cells
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Discovery Vol. 11, No. 5 ( 2021-05-01), p. 1176-1191
    Details
    In: Cancer Discovery, American Association for Cancer Research (AACR), Vol. 11, No. 5 ( 2021-05-01), p. 1176-1191
    Abstract: Although replication repair deficiency, either by mismatch repair deficiency (MMRD) and/or loss of DNA polymerase proofreading, can cause hypermutation in cancer, microsatellite instability (MSI) is considered a hallmark of MMRD alone. By genome-wide analysis of tumors with germline and somatic deficiencies in replication repair, we reveal a novel association between loss of polymerase proofreading and MSI, especially when both components are lost. Analysis of indels in microsatellites (MS-indels) identified five distinct signatures (MS-sigs). MMRD MS-sigs are dominated by multibase losses, whereas mutant-polymerase MS-sigs contain primarily single-base gains. MS deletions in MMRD tumors depend on the original size of the MS and converge to a preferred length, providing mechanistic insight. Finally, we demonstrate that MS-sigs can be a powerful clinical tool for managing individuals with germline MMRD and replication repair–deficient cancers, as they can detect the replication repair deficiency in normal cells and predict their response to immunotherapy. Significance: Exome- and genome-wide MSI analysis reveals novel signatures that are uniquely attributed to mismatch repair and DNA polymerase. This provides new mechanistic insight into MS maintenance and can be applied clinically for diagnosis of replication repair deficiency and immunotherapy response prediction. This article is highlighted in the In This Issue feature, p. 995
    Type of Medium: Online Resource
    ISSN: 2159-8274 , 2159-8290
    URL: Article
    DOI: 10.1158/2159-8290.CD-20-0790
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
    detail.hit.zdb_id: 2607892-2
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  • 3
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    Effect of Low-dose and Standard-dose Aspirin on PGE2 Biosynthesis Among Individuals with Colorectal Adenomas: A Randomized Clinical Trial
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Prevention Research Vol. 13, No. 10 ( 2020-10-01), p. 877-888
    Details
    In: Cancer Prevention Research, American Association for Cancer Research (AACR), Vol. 13, No. 10 ( 2020-10-01), p. 877-888
    Abstract: Low-dose aspirin is recommended by the U.S. Preventive Services Task Force for primary prevention of colorectal cancer in certain individuals. However, broader implementation will require improved precision prevention approaches to identify those most likely to benefit. The major urinary metabolite of PGE2, 11α-hydroxy-9,15-dioxo-2,3,4,5-tetranor-prostane-1,20-dioic acid (PGE-M), is a biomarker for colorectal cancer risk, but it is unknown whether PGE-M is modifiable by aspirin in individuals at risk for colorectal cancer. Adults (N = 180) who recently underwent adenoma resection and did not regularly use aspirin or NSAIDs were recruited to a double-blind, placebo-controlled, randomized trial of aspirin at 81 or 325 mg/day for 8–12 weeks. The primary outcome was postintervention change in urinary PGE-M as measured by LC/MS. A total of 169 participants provided paired urine samples for analysis. Baseline PGE-M excretion was 15.9 ± 14.6 (mean ± S.D, ng/mg creatinine). Aspirin significantly reduced PGE-M excretion (−4.7 ± 14.8) compared with no decrease (0.8 ± 11.8) in the placebo group (P = 0.015; mean duration of treatment = 68.9 days). Aspirin significantly reduced PGE-M levels in participants receiving either 81 (−15%; P = 0.018) or 325 mg/day (−28%; P & lt; 0.0001) compared with placebo. In 40% and 50% of the individuals randomized to 81 or 325 mg/day aspirin, respectively, PGE-M reduction reached a threshold expected to prevent recurrence in 10% of individuals. These results support that aspirin significantly reduces elevated levels of PGE-M in those at increased colorectal cancer risk to levels consistent with lower risk for recurrent neoplasia and underscore the potential utility of PGE-M as a precision chemoprevention biomarker. The ASPIRED trial is registered as NCT02394769.
    Type of Medium: Online Resource
    ISSN: 1940-6207 , 1940-6215
    URL: Article
    DOI: 10.1158/1940-6207.CAPR-20-0216
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
    detail.hit.zdb_id: 2422346-3
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  • 4
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    Five-Year Efficacy and Safety Analysis of the Adenoma Prevention with Celecoxib Trial
    American Association for Cancer Research (AACR) ; 2009
    In:  Cancer Prevention Research Vol. 2, No. 4 ( 2009-04-01), p. 310-321
    Details
    In: Cancer Prevention Research, American Association for Cancer Research (AACR), Vol. 2, No. 4 ( 2009-04-01), p. 310-321
    Abstract: The Adenoma Prevention with Celecoxib Trial examined the efficacy and safety of the cyclooxygenase (Cox)-2 inhibitor, celecoxib, for sporadic colorectal adenoma prevention in patients at high risk for colorectal cancer. The trial randomized 2,035 subjects to receive either placebo, celecoxib 200 mg twice daily, or celecoxib 400 mg twice daily. The primary study safety and efficacy analyses involved 3 years of treatment. The results showed significant antitumor effect but also indicated increased cardiovascular adverse events in patients treated with celecoxib compared with placebo. A total of 933 patients participated in an extension of the Adenoma Prevention with Celecoxib Trial, with a planned total treatment and surveillance duration of 5 years. Study medication was stopped early, resulting in a median treatment duration of 3.1 years for those with a year 5 colonoscopy. Patients treated on the placebo arm had a cumulative adenoma incidence of 68.4% over 5 years of observation. This figure was 59.0% (P & lt; 0.0001) for those receiving low-dose celecoxib, and 60.1% (P & lt; 0.0001) for those receiving high-dose celecoxib. The cumulative incidence of advanced adenomas over 5 years was 21.3% of those taking placebo, 12.5% (P & lt; 0.0001) of those taking low dose celecoxib and 15.8% (P & lt; 0.0001) of those taking high-dose celecoxib. Investigator reported treatment emergent adverse events were similar across all treatment groups for categories including renal and hypertensive events and gastrointestinal ulceration and hemorrhage events. For a category composed of cardiovascular and thrombotic events, the risk relative to placebo was 1.6 (95% confidence interval, 1.0, 2.5) for those using 200 mg twice daily celecoxib and 1.9 (95% confidence interval, 1.2, 3.1) for those using 400 mg twice daily celecoxib. Secondary analysis showed an interaction between a baseline history of atherosclerotic heart disease and study drug use with respect to cardiovascular and thrombotic adverse events (P = 0.004). These results confirm the inhibitory effect of celecoxib on colorectal adenoma formation, and provide additional safety data indicating an elevated risk for cardiovascular and thrombotic adverse events, particularly for patients with preexisting atherosclerotic heart disease.
    Type of Medium: Online Resource
    ISSN: 1940-6207 , 1940-6215
    URL: Article
    DOI: 10.1158/1940-6207.CAPR-08-0206
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2009
    detail.hit.zdb_id: 2422346-3
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  • 5
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    Oncogenic KRAS and BRAF Differentially Regulate Hypoxia-Inducible Factor-1α and -2α in Colon Cancer
    American Association for Cancer Research (AACR) ; 2009
    In:  Cancer Research Vol. 69, No. 21 ( 2009-11-01), p. 8499-8506
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 69, No. 21 ( 2009-11-01), p. 8499-8506
    Abstract: KRAS and BRAF mutations are frequently observed in human colon cancers. These mutations occur in a mutually exclusive manner, and each is associated with distinctive biological features. We showed previously that K-ras can interact with hypoxia to activate multiple signaling pathways. Many hypoxic responses are mediated by hypoxia-inducible factor (HIF)-1α and HIF-2α, and we sought to define the roles of mutant KRAS and BRAF in the induction of HIF-1α and HIF-2α in colon cancer cells. Ectopic expression of mutant K-ras in Caco2 cells enhanced the hypoxic induction of only HIF-1α, whereas mutant BRAF enhanced both HIF-1α and HIF-2α. Knockout or knockdown of mutant KRAS in DLD-1 and HCT116 cells impaired the hypoxic induction of only HIF-1α. HIF-1α mRNA levels were comparable in cells with and without a KRAS mutation. However, the rate of HIF-1α protein synthesis was higher in cells with a KRAS mutation, and this was suppressed by the phosphoinositide 3-kinase inhibitor LY294002. In contrast, knockdown of mutant BRAF in HT29 cells suppressed both HIF-1α and HIF-2α. Although BRAF regulated mRNA levels of both HIF-1α and HIF-2α, knockdown of BRAF or treatment with the MEK inhibitor PD98059 impaired the translation of only HIF-2α. Our data reveal that oncogenic KRAS and BRAF mutations differentially regulate the hypoxic induction of HIF-1α and HIF-2α in colon cancer, and this may potentially contribute to the phenotypic differences of KRAS and BRAF mutations in colon tumors. [Cancer Res 2009;69(21):8499–506]
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-09-2213
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2009
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 6
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    Abstract 3440: Activation of hedgehog pathway in tumor vasculature is a late event of pancreatic tumorigenesis
    American Association for Cancer Research (AACR) ; 2010
    In:  Cancer Research Vol. 70, No. 8_Supplement ( 2010-04-15), p. 3440-3440
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 8_Supplement ( 2010-04-15), p. 3440-3440
    Abstract: Bone marrow cells can be activated to function as instigators of tumor growth by systemic tumor-derived signals. We have identified subsets of BM cells that regulate neovascularization in pancreatic ductal adenocarcinoma (PDAC). Notably, blockade of Hedgehog (Hh) signaling markedly destabilized neovessels in PDAC xenografts by attenuating the homing and incorporation of the BM-derived cells into the neovasculature. We found IGF-1 production in the tumor stroma was regulated by the Hh ligand, Shh, and played a key role during this process. In vitro co-culture experiments demonstrated that human PDAC cell lines induced IGF-1 in c-Kit+ BM derived mononuclear cells utilized as pro-angiogenic cells, and that the induction was attenuated either by cyclopamine or expression of shRNA targeting Smo in the mononuclear cells. Shh secreted from PDAC cells induced tube formation by the mouse endothelial line MS-1, suggesting an important role for Shh in migration and capillary formation of the BM-derived pro-angiogenic cells; this induction of capillary morphogenesis was blocked by anti-IGF-1 neutralizing antibody. The “paracrine” effect of Hh seems to be a late event during pancreatic tumorigenesis, as full length Gli2 expression in neovasculatures was detected within PDAC lesions, but not in precursor PanIN lesions using a genetically engineered mouse models. We also observed upregulation of VE-cadherin, Id1, and Ptch1 mRNA in lineage-/c-Kit+ fraction of BM mononuclear cells from PDAC mice as compared to control mice or mice with PanIN, suggesting that pro-angiogenic conditions induced at the level of the BM in cancer-bearing hosts. The primitive progenitors derived from ‘activated BM’ are imported to the tumor microenvironment where they become fully activated. Overall, these studies provide insights into the cellular and molecular mechanisms by which BM-derived cells promote tumor growth and angiogenesis and have implications for the design of anti-angiogenesis therapies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3440.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM10-3440
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 7
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    Cost-Effectiveness of Prophylactic Surgery for Duodenal Cancer in Familial Adenomatous Polyposis
    American Association for Cancer Research (AACR) ; 2009
    In:  Cancer Epidemiology, Biomarkers & Prevention Vol. 18, No. 10 ( 2009-10-01), p. 2677-2684
    Details
    In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 18, No. 10 ( 2009-10-01), p. 2677-2684
    Abstract: Background: Duodenal cancer is the leading cause of cancer death in familial adenomatous polyposis after colorectal cancer. The lifetime risk for developing duodenal cancer is 4% to 10%. Current treatment guidelines recommend endoscopic surveillance with a prophylactic pancreaticoduodenectomy in advanced duodenal polyposis, defined using the Spigelman staging system. Because no clinical trials have assessed this recommendation, a modeling approach was used to evaluate the cost-effectiveness of various treatment strategies. Methods: A Markov model was constructed to estimate the life expectancy and cost of three different strategies: pancreaticoduodenectomy at Spigelman stage III, pancreaticoduodenectomy at Spigelman stage IV, and pancreaticoduodenectomy at cancer diagnosis. A cohort of 30-year-old familial adenomatous polyposis patients with total colectomies was simulated until age 80. The analysis was from a societal perspective. Extensive sensitivity analysis was performed to assess the impact of model uncertainty on results. Results: At all stages of polyposis and all ages & lt;80 years, prophylactic surgery at Spigelman stage IV resulted in the greatest life expectancy. Surgery at stage IV was more effective and more expensive than surgery at cancer diagnosis, with an incremental cost of $3,200 per quality-adjusted life year gained. Surgery at stage III was not a viable option. The results were robust to wide variation in model parameters but were sensitive to the post-pancreaticoduodenectomy quality of life score. Conclusions: Prophylactic pancreaticoduodenectomy at stage IV duodenal polyposis in familial adenomatous polyposis is a cost-effective approach that results in greater life expectancy than surgery at either stage III or cancer diagnosis. (Cancer Epidemiol Biomarkers Prev 2009;18(10):2677–84)
    Type of Medium: Online Resource
    ISSN: 1055-9965 , 1538-7755
    URL: Article
    DOI: 10.1158/1055-9965.EPI-09-0153
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2009
    detail.hit.zdb_id: 2036781-8
    detail.hit.zdb_id: 1153420-5
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  • 8
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    Direct Evidence that Bevacizumab, an Anti-VEGF Antibody, Up-regulates SDF1α, CXCR4, CXCL6, and Neuropilin 1 in Tumors from Patients with Rectal Cancer
    American Association for Cancer Research (AACR) ; 2009
    In:  Cancer Research Vol. 69, No. 20 ( 2009-10-15), p. 7905-7910
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 69, No. 20 ( 2009-10-15), p. 7905-7910
    Abstract: Clinical studies converge on the observation that circulating cytokines are elevated in most cancer patients by anti–vascular endothelial growth factor (VEGF) therapy. However, the source of these molecules and their relevance in tumor escape remain unknown. We examined the gene expression profiles of cancer cells and tumor-associated macrophages in tumor biopsies before and 12 days after monotherapy with the anti-VEGF antibody bevacizumab in patients with rectal carcinoma. Bevacizumab up-regulated stromal cell–derived factor 1α (SDF1α), its receptor CXCR4, and CXCL6, and down-regulated PlGF, Ang1, and Ang2 in cancer cells. In addition, bevacizumab decreased Ang1 and induced neuropilin 1 (NRP1) expression in tumor-associated macrophages. Higher SDF1α plasma levels during bevacizumab treatment significantly associated with distant metastasis at three years. These data show that VEGF blockade up-regulates inflammatory pathways and NRP1, which should be evaluated as potential targets for improving anti-VEGF therapy. [Cancer Res 2009;69(20):7905–10]
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-09-2099
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2009
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 9
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    Hypoxia-Inducible Factor-1-Independent Regulation of Vascular Endothelial Growth Factor by Hypoxia in Colon Cancer
    American Association for Cancer Research (AACR) ; 2004
    In:  Cancer Research Vol. 64, No. 5 ( 2004-03-01), p. 1765-1772
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 64, No. 5 ( 2004-03-01), p. 1765-1772
    Abstract: The induction of vascular endothelial growth factor (VEGF) is an essential feature of tumor angiogenesis, and the hypoxia-inducible factor-1 (HIF-1) transcription factor is known to be a key mediator of this process. In colon cancer, the frequently mutated K-ras oncogene also can regulate VEGF expression, but the role that K-ras may play in hypoxia is unknown. Hypoxia induced VEGF promoter activity, mRNA, and protein levels in colon cancer cells. Although HIF-1α was induced by hypoxia, VEGF reporter constructs with selectively mutated hypoxia-response elements remained responsive to hypoxia. In addition, “knockdown” of HIF-1α by RNA interference only minimally inhibited the hypoxic induction of VEGF. A region of the VEGF promoter between −420 and −90 bp mediated this HIF-independent induction by hypoxia. The introduction of K-rasVal12 augmented the hypoxic induction of VEGF, and this was observed in wild-type and HIF-1α knockdown colon cancer cells. Thus, VEGF may be induced by hypoxia through HIF-dependent and HIF-independent pathways, and K-ras also can induce VEGF in hypoxia independent of HIF-1. These findings suggest the existence of multiple mechanisms regulating the hypoxic induction of VEGF in colon cancer.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-03-3017
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2004
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 10
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    Abstract B115: The epithelial to mesenchymal transition is impaired in colon cancer cells with microsatellite instability
    American Association for Cancer Research (AACR) ; 2009
    In:  Molecular Cancer Therapeutics Vol. 8, No. 12_Supplement ( 2009-12-10), p. B115-B115
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 8, No. 12_Supplement ( 2009-12-10), p. B115-B115
    Abstract: Colorectal cancers (CRC) displaying DNA microsatellite instability (MSI) are associated with a favorable natural history, but the molecular basis for this observation has not been defined. We sought to determine whether the epithelial-to-mesenchymal transition (EMT), a highly conserved process involved in embryogenesis as well as in tumor progression, invasion, and metastasis, is impaired in MSI-positive CRCs that characteristically have a mutant transforming growth factor-β receptor type II (TGFBR2) gene. The induction of EMT by TGF-β1 was analyzed by phase contrast microscopy, immunofluorescence, qRT-PCR, immunoblotting, and cellular migration and invasion assays in MSS (SW480 and HT29) and MSI (DLD1 and HCT116) colon cancer cell lines. Expression of epithelial (E-cadherin) and mesenchymal (vimentin and N-cadherin) markers was evaluated by immunohistochemistry and qRT-PCR in 129 human colorectal tumors. TGF-β1 induced changes in cellular morphology from an epithelial to a fibroblasticlike morphology, changes in gene and protein expression with a reduction in E-cadherin and induction of vimentin, and changes in motility and invasion consistent with the occurrence of EMT only in MSS colon cancer cells. These effects did not require Smad4 but depended upon the recruitment of ERK. Cells with MSI and mutant TGFBR2 failed to exhibit any of these changes in response to TGF-β1. However, tumor cells with MSI but wildtype TGFBR2 underwent EMT in response to TGF-β1, indicating that TGFBR2 genotype is a key determinant of the EMT response in tumors with MSI. In human colorectal tumors, expression of the EMT markers N-cadherin and vimentin was significantly associated with adverse clinicopathologic features and the absence of MSI. These findings define a unique genotype-phenotype relationship between TGFBR2 and EMT that may contribute to the improved prognosis consistently observed in colon cancers with MSI. Furthermore, these results suggest a potential rationale for the therapeutic inhibition of TGF-β signaling in MSS colorectal tumors. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B115.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-09-B115
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2009
    detail.hit.zdb_id: 2062135-8
    SSG: 12
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