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Ali H. Future incidence and mortality of colorectal carcinoma in the United States: an updated overview of risk factors and preventative measures. EXPLORATION OF MEDICINE 2021. [DOI: 10.37349/emed.2021.00063] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
According to the Global Cancer Observatory (GLOBOCAN) 2020, colorectal carcinoma (CRC) was the second leading cause of cancer death globally. Current literature utilizes reported databases such as Surveillance, Epidemiology, and End Results (SEER) to better understand the epidemiology of CRC. The global cancer observatory’s “Cancer Tomorrow” data visualization tools was used to predict the future incidence and mortality of colorectal cancers until 2030 as a guided tool to look over ways to reduce incidence by controlling risk factors of CRC. The total number of CRC is expected to rise by 2030, with a percent change of 17.3%. The expected percent change in colon cancer is more than rectal cancer (19.8% vs. 11.6%). The estimated number of deaths secondary to CRC is expected to increase in 2030, an estimated percent change of 22.2%. The incidence and mortality rate was higher in men vs. women; however, the gap seems to be closing on trend analysis. Major risk factors for CRC include familial syndromes, family history, race, gender, obesity, diet, alcohol, and smoking. Risk can be reduced by exercise and dietary changes, fiber intake, vitamin D, calcium, and minerals. Individualized screening based on age, gender, and additional risk factors could be an option that needs further comparative data to propose a definitive benefit over established screening guidelines.
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Affiliation(s)
- Hassam Ali
- Department of Internal Medicine, East Carolina University/Vidant Medical Center, Greenville, NC 27834, USA
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2
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Tschernichovsky R, Katz LH, Derazne E, Berliner MBZ, Simchoni M, Levine H, Keinan-Boker L, Benouaich-Amiel A, Kanner AA, Laviv Y, Honig A, Dudnik E, Siegal T, Mandel J, Twig G, Yust-Katz S. Height in adolescence as a risk factor for glioma subtypes: a nationwide retrospective cohort study of 2.2 million subjects. Neuro Oncol 2021; 23:1383-1392. [PMID: 33631004 DOI: 10.1093/neuonc/noab049] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Gliomas manifest in a variety of histological phenotypes with varying aggressiveness. The etiology of glioma remains largely unknown. Taller stature in adulthood has been linked with glioma risk. The aim of this study was to discern whether this association can be detected in adolescence. METHODS The cohort included 2 223 168 adolescents between the ages of 16 and 19 years. Anthropometric measurements were collected at baseline. Incident cases of glioma were extracted from the Israel National Cancer Registry over a follow-up period spanning 47 635 745 person-years. Cox proportional hazard models were used to estimate the hazard ratio (HR) for glioma and glioma subtypes according to height, body mass index (BMI), and sex. RESULTS A total of 1195 patients were diagnosed with glioma during the study period. Mean (SD) age at diagnosis was 38.1 (11.7) years. Taller adolescent height (per 10-cm increase) was positively associated with the risk for glioma of any type (HR: 1.15; P = .002). The association was retained in subgroup analyses for low-grade glioma (HR: 1.17; P = .031), high-grade glioma (HR: 1.15; P = .025), oligodendroglioma (HR: 1.31; P = .015), astrocytoma (HR: 1.12; P = .049), and a category of presumed IDH-mutated glioma (HR: 1.17; P = .013). There was a trend toward a positive association between height and glioblastoma, however this had borderline statistical significance (HR: 1.15; P = .07). After stratification of the cohort by sex, height remained a risk factor for men but not for women. CONCLUSIONS The previously established association between taller stature in adulthood and glioma risk can be traced back to adolescence. The magnitude of association differs by glioma subtype.
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Affiliation(s)
- Roi Tschernichovsky
- Neuro-Oncology Unit, Davidoff Cancer Center, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Lior H Katz
- Department of Gastroenterology and Hepatology, Hadassah Hebrew University Medical Center, Jerusalem, Israel
| | - Estela Derazne
- Neuro-Oncology Unit, Davidoff Cancer Center, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Matan Ben-Zion Berliner
- Neuro-Oncology Unit, Davidoff Cancer Center, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Maya Simchoni
- Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Hagai Levine
- Braun School of Public Health and Community Medicine, Hadassah University Hospital - Ein Kerem, Jerusalem, Israel
| | - Lital Keinan-Boker
- Israel Center for Disease Control, Israel Ministry of Health, Ramat Gan, Israel.,School of Public Health, University of Haifa, Haifa, Israel
| | - Alexandra Benouaich-Amiel
- Neuro-Oncology Unit, Davidoff Cancer Center, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel
| | - Andrew A Kanner
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.,Department of Neurosurgery, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel
| | - Yosef Laviv
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.,Department of Neurosurgery, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel
| | - Asaf Honig
- Department of Military Medicine, Faculty of Medicine, Hebrew University of Jerusalem and the Israel Defense Forces Medical Corps, Ramat Gan, Israel
| | - Elizabeth Dudnik
- Neuro-Oncology Unit, Davidoff Cancer Center, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Tali Siegal
- Neuro-Oncology Unit, Davidoff Cancer Center, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel
| | - Jacob Mandel
- Department of Military Medicine, Faculty of Medicine, Hebrew University of Jerusalem and the Israel Defense Forces Medical Corps, Ramat Gan, Israel
| | - Gilad Twig
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.,Institute of Endocrinology, Sheba Medical Center, Tel HaShomer, Israel
| | - Shlomit Yust-Katz
- Neuro-Oncology Unit, Davidoff Cancer Center, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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Crudele L, Piccinin E, Moschetta A. Visceral Adiposity and Cancer: Role in Pathogenesis and Prognosis. Nutrients 2021; 13:2101. [PMID: 34205356 PMCID: PMC8234141 DOI: 10.3390/nu13062101] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 06/14/2021] [Accepted: 06/16/2021] [Indexed: 12/11/2022] Open
Abstract
The prevalence of being overweight and obese has been expanded dramatically in recent years worldwide. Obesity usually occurs when the energetic introit overtakes energy expenditure from metabolic and physical activity, leading to fat accumulation mainly in the visceral depots. Excessive fat accumulation represents a risk factor for many chronic diseases, including cancer. Adiposity, chronic low-grade inflammation, and hyperinsulinemia are essential factors of obesity that also play a crucial role in tumor onset. In recent years, several strategies have been pointed toward boundary fat accumulation, thus limiting the burden of cancer attributable to obesity. While remodeling fat via adipocytes browning seems a tempting prospect, lifestyle interventions still represent the main pathway to prevent cancer and enhance the efficacy of treatments. Specifically, the Mediterranean Diet stands out as one of the best dietary approaches to curtail visceral adiposity and, therefore, cancer risk. In this Review, the close relationship between obesity and cancer has been investigated, highlighting the biological mechanisms at the basis of this link. Finally, strategies to remodel fat, including browning and lifestyle interventions, have been taken into consideration as a major perspective to limit excess body weight and tumor onset.
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Affiliation(s)
- Lucilla Crudele
- Department of Interdisciplinary Medicine, University of Bari “Aldo Moro”, 70124 Bari, Italy; (L.C.); (E.P.)
- Department of Biomedical Sciences and Human Oncology, University of Bari “Aldo Moro”, 70124 Bari, Italy
| | - Elena Piccinin
- Department of Interdisciplinary Medicine, University of Bari “Aldo Moro”, 70124 Bari, Italy; (L.C.); (E.P.)
- Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari “Aldo Moro”, 70124 Bari, Italy
| | - Antonio Moschetta
- Department of Interdisciplinary Medicine, University of Bari “Aldo Moro”, 70124 Bari, Italy; (L.C.); (E.P.)
- INBB, National Institute for Biostructures and Biosystems, 00136 Rome, Italy
- National Cancer Center, IRCCS Istituto Tumori Giovanni Paolo II, 70124 Bari, Italy
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Abstract
PURPOSE OF REVIEW This review summarizes a selection of epidemiologic research assessing the associations between carbohydrate intake and cancer incidence and survival. Evidence for plausible biological mechanisms is also considered. RECENT FINDINGS The mechanistic paradigm explaining the relationship between carbohydrates and cancer risk has been contested by numerous observational studies. Carbohydrates have conventionally been ascribed a deleterious role in the field of cancer research due to previous preclinical findings. A breadth of studies suggests that complex carbohydrate intake is inversely associated with risk of a number of cancer types. Data from studies assessing simple carbohydrates and cancer risk are mixed. Furthermore, recommendations for subsequent studies are framed.
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Affiliation(s)
- Christian A Maino Vieytes
- Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, 905 S Goodwin Ave, 386 Bevier Hall, Urbana, IL, 61801, USA
| | - Hania M Taha
- Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaig, Urbana, IL, USA
| | - Amirah A Burton-Obanla
- Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, 905 S Goodwin Ave, 386 Bevier Hall, Urbana, IL, 61801, USA
| | - Katherine G Douglas
- Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaig, Urbana, IL, USA
| | - Anna E Arthur
- Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, 905 S Goodwin Ave, 386 Bevier Hall, Urbana, IL, 61801, USA.
- Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaig, Urbana, IL, USA.
- Carle Cancer Center, Carle Foundation Hospital, Urbana, IL, USA.
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5
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Hang D, He X, Kværner AS, Chan AT, Wu K, Ogino S, Hu Z, Shen H, Pollak MN, Giovannucci EL, Song M. Plasma Biomarkers of Insulin and the Insulin-like Growth Factor Axis, and Risk of Colorectal Adenoma and Serrated Polyp. JNCI Cancer Spectr 2019; 3:pkz056. [PMID: 32328558 PMCID: PMC7050032 DOI: 10.1093/jncics/pkz056] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Revised: 06/11/2019] [Accepted: 07/26/2019] [Indexed: 01/16/2023] Open
Abstract
BACKGROUND Hyperinsulinemia, high insulin-like growth factor 1 (IGF1) levels, and low IGF binding protein 1 (IGFBP1) levels have been implicated in the relationship between obesity and increased risk of colorectal cancer (CRC). However, it remains inconclusive whether circulating biomarkers of insulin and the IGF axis are associated with conventional adenoma and serrated polyp, the two distinct groups of CRC precursors. METHODS We prospectively examined the associations of plasma C-peptide, IGF1, IGFBP1, IGFBP3, and IGF1 to IGFBP3 ratio with conventional adenoma and serrated polyp among 11 072 women from the Nurses' Health Studies. Multivariable logistic regression was used to calculate the odds ratio (OR) per 1-SD increase in each biomarker for overall risk of conventional adenoma and serrated polyp and according to polyp feature. RESULTS During 20 years of follow-up, we documented 1234 conventional adenomas and 914 serrated polyps. After adjusting for various lifestyle factors (including body mass index), higher concentrations of IGFBP1 were associated with lower risk of serrated polyp (OR = 0.84, 95% confidence interval = 0.75 to 0.95, P = .005). The association was particularly strong for large serrated polyp (≥10 mm) located in the distal colon and rectum (OR = 0.59, 95% confidence interval = 0.39 to 0.87, P = .01). In contrast, we did not find any statistically significant association between the biomarkers and conventional adenoma. CONCLUSIONS A higher plasma level of IGFBP1 was associated with lower risk of serrated polyp. Our findings support a potential role of IGFBP1 in the serrated pathway of CRC in women.
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Affiliation(s)
- Dong Hang
- Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, China
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA
| | - Xiaosheng He
- Clinical and Translational Epidemiology Unit and Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA
- Department of Colorectal Surgery, the Six Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Ane Sørlie Kværner
- Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
| | - Andrew T Chan
- Clinical and Translational Epidemiology Unit and Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA
| | - Kana Wu
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA
| | - Shuji Ogino
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA
- Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA
- Program in Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA
| | - Zhibin Hu
- Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Hongbing Shen
- Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Michael N Pollak
- Department of Oncology, McGill University, Montreal, Quebec, Canada
| | - Edward L Giovannucci
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA
| | - Mingyang Song
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA
- Clinical and Translational Epidemiology Unit and Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA
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Gadelha MR, Kasuki L, Lim DST, Fleseriu M. Systemic Complications of Acromegaly and the Impact of the Current Treatment Landscape: An Update. Endocr Rev 2019; 40:268-332. [PMID: 30184064 DOI: 10.1210/er.2018-00115] [Citation(s) in RCA: 206] [Impact Index Per Article: 34.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2018] [Accepted: 07/26/2018] [Indexed: 12/19/2022]
Abstract
Acromegaly is a chronic systemic disease with many complications and is associated with increased mortality when not adequately treated. Substantial advances in acromegaly treatment, as well as in the treatment of many of its complications, mainly diabetes mellitus, heart failure, and arterial hypertension, were achieved in the last decades. These developments allowed change in both prevalence and severity of some acromegaly complications and furthermore resulted in a reduction of mortality. Currently, mortality seems to be similar to the general population in adequately treated patients with acromegaly. In this review, we update the knowledge in complications of acromegaly and detail the effects of different acromegaly treatment options on these complications. Incidence of mortality, its correlation with GH (cumulative exposure vs last value), and IGF-I levels and the shift in the main cause of mortality in patients with acromegaly are also addressed.
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Affiliation(s)
- Mônica R Gadelha
- Neuroendocrinology Research Center/Endocrine Section and Medical School, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.,Neuroendocrine Section, Instituto Estadual do Cérebro Paulo Niemeyer, Secretaria Estadual de Saúde do Rio de Janeiro, Rio de Janeiro, Brazil.,Neuropathology and Molecular Genetics Laboratory, Instituto Estadual do Cérebro Paulo Niemeyer, Rio de Janeiro, Brazil
| | - Leandro Kasuki
- Neuroendocrinology Research Center/Endocrine Section and Medical School, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.,Neuroendocrine Section, Instituto Estadual do Cérebro Paulo Niemeyer, Secretaria Estadual de Saúde do Rio de Janeiro, Rio de Janeiro, Brazil.,Endocrine Unit, Hospital Federal de Bonsucesso, Rio de Janeiro, Brazil
| | - Dawn S T Lim
- Department of Endocrinology, Singapore General Hospital, Singapore, Singapore
| | - Maria Fleseriu
- Department of Endocrinology, Diabetes and Metabolism, Oregon Health and Science University, Portland, Oregon.,Department of Neurological Surgery, Oregon Health and Science University, Portland, Oregon.,Northwest Pituitary Center, Oregon Health and Science University, Portland, Oregon
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7
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Fibroblast growth factor 21 as a circulating biomarker at various stages of colorectal carcinogenesis. Br J Cancer 2018; 119:1374-1382. [PMID: 30425347 PMCID: PMC6265243 DOI: 10.1038/s41416-018-0280-x] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Revised: 08/14/2018] [Accepted: 09/10/2018] [Indexed: 12/17/2022] Open
Abstract
Background Despite evidence that inflammation and metabolism play a crucial role in colorectal carcinogenesis, there have been few studies on the association of inflammatory and metabolic protein biomarkers in various stages of colorectal carcinogenesis. Methods Ninety-two inflammatory and metabolic biomarkers were measured in plasma samples of participants of screening colonoscopy. Markers identified to be significantly associated with the presence of advanced colorectal neoplasia (ACN) in a discovery set (n = 204) were validated in an independent replication set (n = 422). Adjusted associations with the presence of non-advanced adenomas (NAA), advanced precancerous lesions (APL) and colorectal cancer (CRC) were quantified by multiple logistic regression. Results Out of the 92 inflammatory proteins, 72 markers were evaluable and 8 showed statistically significant associations with the odds of ACN after full adjustment for potential risk factors for CRC in the discovery set. One of these, fibroblast growth factor 21 (FGF-21), could be validated in the replication set. The multivariable-adjusted odds ratio (OR) reached 2.65 (95% CI, 1.50–4.81) for individuals with FGF-21 levels within the highest tertile, compared to those within the lowest tertile (Ptrend across tertiles = 0.001). Separate models revealed fully adjusted ORs for NAA, APL and CRC of 2.99 (95% CI, 1.45–6.58, Ptrend = 0.005), 2.24 (95% CI, 1.18–4.44, Ptrend = 0.021) and 3.92 (95% CI, 1.51–12.18, Ptrend = 0.003), respectively. Conclusions Circulating FGF-21 level is associated with increased risk of early and late stages of colorectal carcinogenesis, supporting a role of inflammation and metabolism at all stages of colorectal carcinogenesis, and suggesting potential use of this biomarker for risk stratification in CRC screening.
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8
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Lee H, Kim N, Yoo YJ, Kim H, Jeong E, Choi S, Moon SU, Oh SH, Mills GB, Yoon S, Kim WY. β-catenin/TCF activity regulates IGF-1R tyrosine kinase inhibitor sensitivity in colon cancer. Oncogene 2018; 37:5466-5475. [PMID: 29895971 DOI: 10.1038/s41388-018-0362-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2017] [Revised: 05/06/2018] [Accepted: 05/25/2018] [Indexed: 12/19/2022]
Abstract
The availability of large-scale drug screening data on cell line panels provides a unique opportunity to identify predictive biomarkers for targeted drug efficacy. Analysis of diverse drug data on ~990 cancer cell lines revealed enhanced sensitivity of insulin-like growth factor 1 receptor/ Insulin Receptor (IGF-1R/IR) tyrosine kinase inhibitors (TKIs) in colon cancer cells. Interestingly, β-catenin/TCF(T cell factor)-responsive promoter activity exhibited a significant positive association with IGF-1R/IR TKI response, while the mutational status of direct upstream genes, such as CTNNB1 and APC, was not significantly associated with the response. The β-catenin/TCF activity high cell lines express components of IGF-1R/IR signaling more than the low cell lines explaining their enhanced sensitivity against IGF-1R/IR TKI. Reinforcing β-catenin/TCF responsive promoter activity by introducing CTNNB1 gain-of-function mutations into IGF-1R/IR TKI-resistant cells increased the expression and activity of IGF-1R/IR signaling components and also sensitized the cells to IGF-1R/IR TKIs in vitro and in vivo. Analysis of TCGA data revealed that the stronger β-catenin/TCF responsive promoter activity was associated with higher IGF-1R and IGF2 transcription in human colon cancer specimens as well. Collectively, compared to the mutational status of upstream genes, β-catenin/TCF responsive promoter activity has potential to be a stronger predictive positive biomarker for IGF-1R/IR TKI responses in colon cancer cells. The present study highlights the potential of transcriptional activity as therapeutic biomarkers for targeted therapies, overcoming the limited ability of upstream genetic mutations to predict responses.
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Affiliation(s)
- Hani Lee
- Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University, Seoul, 04310, Republic of Korea.,Center for Advanced Bioinformatics & Systems Medicine, Sookmyung Women's University, Seoul, 04310, Republic of Korea
| | - Nayoung Kim
- Center for Advanced Bioinformatics & Systems Medicine, Sookmyung Women's University, Seoul, 04310, Republic of Korea.,Department of Biological Sciences, Sookmyung Women's University, Seoul, 04310, Republic of Korea
| | - Young Ji Yoo
- Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University, Seoul, 04310, Republic of Korea.,Center for Advanced Bioinformatics & Systems Medicine, Sookmyung Women's University, Seoul, 04310, Republic of Korea
| | - Hyejin Kim
- Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University, Seoul, 04310, Republic of Korea.,Center for Advanced Bioinformatics & Systems Medicine, Sookmyung Women's University, Seoul, 04310, Republic of Korea
| | - Euna Jeong
- Center for Advanced Bioinformatics & Systems Medicine, Sookmyung Women's University, Seoul, 04310, Republic of Korea
| | - SeokGyeong Choi
- Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University, Seoul, 04310, Republic of Korea.,Center for Advanced Bioinformatics & Systems Medicine, Sookmyung Women's University, Seoul, 04310, Republic of Korea
| | - Sung Un Moon
- Center for Advanced Bioinformatics & Systems Medicine, Sookmyung Women's University, Seoul, 04310, Republic of Korea
| | - Seung Hyun Oh
- College of Pharmacy, Gachon University, Incheon, 21936, Republic of Korea
| | - Gordon B Mills
- Systems Biology, MD Anderson Cancer Center, University of Texas, Houston, TX, 77030, USA
| | - Sukjoon Yoon
- Center for Advanced Bioinformatics & Systems Medicine, Sookmyung Women's University, Seoul, 04310, Republic of Korea. .,Department of Biological Sciences, Sookmyung Women's University, Seoul, 04310, Republic of Korea.
| | - Woo-Young Kim
- Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University, Seoul, 04310, Republic of Korea. .,Center for Advanced Bioinformatics & Systems Medicine, Sookmyung Women's University, Seoul, 04310, Republic of Korea.
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9
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Abstract
Humans and other mammals are colonized by microbial agents across the kingdom which can represent a unique microbiome pattern. Dysbiosis of the microbiome has been associated with pathology including cancer. We have identified a microbiome signature unique to ovarian cancers, one of the most lethal malignancies of the female reproductive system, primarily because of its asymptomatic nature during the early stages in development. We screened ovarian cancer samples along with matched, and non-matched control samples using our pan-pathogen array (PathoChip), combined with capture-next generation sequencing. The results show a distinct group of viral, bacterial, fungal and parasitic signatures of high significance in ovarian cases. Further analysis shows specific viral integration sites within the host genome of tumor samples, which may contribute to the carcinogenic process. The ovarian cancer microbiome signature provides insights for the development of targeted therapeutics against ovarian cancers.
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10
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Chan YX, Alfonso H, Paul Chubb SA, Ho KKY, Gerard Fegan P, Hankey GJ, Golledge J, Flicker L, Yeap BB. Higher IGFBP3 is associated with increased incidence of colorectal cancer in older men independently of IGF1. Clin Endocrinol (Oxf) 2018; 88:333-340. [PMID: 29044573 DOI: 10.1111/cen.13499] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2017] [Revised: 10/02/2017] [Accepted: 10/11/2017] [Indexed: 12/22/2022]
Abstract
OBJECTIVE Insulin-like growth factor 1 (IGF1) has anabolic and growth-promoting effects, raising concerns regarding its potential to promote tumour growth. Circulating IGF1 is bound to binding proteins, which modulate bioavailability of IGF1. This study assessed the associations of IGF1 and its binding proteins 1 (IGFBP1) and 3 (IGFBP3) with cancer risk. DESIGN A prospective cohort study of 4042 men aged ≥70 years. METHODS Plasma total IGF1, IGFBP1 and IGFBP3 were measured between 2001 and 2004. Cancer-related outcomes were assessed until 20 June 2013 using data linkage. Analyses were performed using proportional hazards models with death as a competing risk, and adjustments were made for potential confounders. Results are expressed as subhazard ratios (SHR). RESULTS There were 907 men who were diagnosed with cancer during a median of 9-year follow-up. Of these, there were 359, 139 and 125 prostate, colorectal and lung cancers, respectively. After adjustments, total IGF1 was not associated with the incidence of any cancer, prostate, lung or colorectal cancer. In the fully-adjusted model, higher IGFBP3 was associated with increased incidence of colorectal cancer (SHR = 1.20, 95% CI 1.01-1.43; P = .041 for every 1 standard deviation increase in IGFBP3) but not other cancers. This effect was not attenuated by inclusion of total IGF1 into the multivariate model (SHR = 1.28, 95% CI 1.03-1.58; P = .025). Neither total IGF1, IGFBP1 nor IGFBP3 were associated with cancer-related deaths. CONCLUSION Higher IGFBP3 predicted increased incidence of colorectal cancer in older men independent of conventional risk factors and total IGF1. Further studies are warranted to explore potential underlying mechanisms.
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Affiliation(s)
- Yi X Chan
- School of Medicine, University of Western Australia, Perth, WA, Australia
- Department of Endocrinology and Diabetes, Fiona Stanley Hospital, Perth, WA, Australia
| | - Helman Alfonso
- School of Public Health, Department of Epidemiology and Biostatistics, Curtin University, Perth, WA, Australia
| | - Stephen Anthony Paul Chubb
- School of Medicine, University of Western Australia, Perth, WA, Australia
- Pathwest Laboratory Medicine, Fiona Stanley Hospital, Perth, WA, Australia
| | - Ken K Y Ho
- Department of Diabetes and Endocrinology, Princess Alexandra Hospital, Brisbane, QLD, Australia
| | - Peter Gerard Fegan
- Department of Endocrinology and Diabetes, Fiona Stanley Hospital, Perth, WA, Australia
| | - Graeme J Hankey
- School of Medicine, University of Western Australia, Perth, WA, Australia
- Department of Neurology, Sir Charles Gairdner Hospital, Perth, WA, Australia
| | - Jonathan Golledge
- Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, QLD, Australia
- Department of Vascular and Endovascular Surgery, The Townsville Hospital, Townsville, QLD, Australia
| | - Leon Flicker
- School of Medicine, University of Western Australia, Perth, WA, Australia
- Western Australian Centre for Health and Ageing, Centre for Medical Research, University of Western Australia, Perth, WA, Australia
| | - Bu B Yeap
- School of Medicine, University of Western Australia, Perth, WA, Australia
- Department of Endocrinology and Diabetes, Fiona Stanley Hospital, Perth, WA, Australia
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Jasim S, Alahdab F, Ahmed AT, Tamhane SU, Sharma A, Donegan D, Nippoldt TB, Murad MH. The effect of growth hormone replacement in patients with hypopituitarism on pituitary tumor recurrence, secondary cancer, and stroke. Endocrine 2017; 56:267-278. [PMID: 27815769 DOI: 10.1007/s12020-016-1156-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2016] [Accepted: 10/18/2016] [Indexed: 12/29/2022]
Abstract
Growth hormone replacement therapy has benefits for patients with hypopituitarism. The safety profile in regard to tumor recurrence or progression, development of secondary malignancies, or cerebrovascular stroke is still an area of debate. A comprehensive search of multiple databases-MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus was conducted through August 2015. Eligible studies that evaluated long-term adverse events in adult patients with hypopituitarism treated with growth hormone replacement therapy and reported development of pituitary tumor recurrence or progression, secondary malignancies, or cerebrovascular stroke were selected following a predefined protocol. Reviewers, independently and in duplicate, extracted data and assessed the risk of bias. Random-effects meta-analysis was used to pool relative risks and 95 % confidence intervals. We included 15 studies (published 1995-2015) that reported on 46,148 patients. Compared to non-replacement, growth hormone replacement therapy in adults with hypopituitarism was not associated with statistically significant change in pituitary tumor progression or recurrence (relative risk, 0.77; 95 % confidence interval, 0.53-1.13) or development of secondary malignancy (relative risk, 0.99; 95 % confidence interval, 0.70-1.39). In two retrospective studies, there was higher risk of stroke in patients who did not receive replacement (relative risk, 2.07; 95 % confidence interval, 1.51-2.83). The quality of evidence is low due to study limitations and imprecision. This systematic review and meta-analysis supports the overall safety of growth hormone therapeutic use in adults with hypopituitarism with no clear evidence of increased risk of pituitary tumor recurrence, malignancy, or stroke.
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Affiliation(s)
- Sina Jasim
- Division of Endocrinology, Diabetes, Metabolism, & Nutrition, Mayo Clinic, Rochester, MN, USA
| | - Fares Alahdab
- Mayo Clinic Evidence-Based Practice Center, Rochester, MN, USA
| | - Ahmed T Ahmed
- Mayo Clinic Evidence-Based Practice Center, Rochester, MN, USA
| | - Shrikant U Tamhane
- Division of Endocrinology, Diabetes, Metabolism, & Nutrition, Mayo Clinic, Rochester, MN, USA
| | - Anu Sharma
- Division of Endocrinology, Diabetes, Metabolism, & Nutrition, Mayo Clinic, Rochester, MN, USA
| | - Diane Donegan
- Division of Endocrinology, Diabetes, Metabolism, & Nutrition, Mayo Clinic, Rochester, MN, USA
| | - Todd B Nippoldt
- Division of Endocrinology, Diabetes, Metabolism, & Nutrition, Mayo Clinic, Rochester, MN, USA
| | - M Hassan Murad
- Mayo Clinic Evidence-Based Practice Center, Rochester, MN, USA.
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12
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Bandettini WP, Karageorgiadis AS, Sinaii N, Rosing DR, Sachdev V, Schernthaner-Reiter MH, Gourgari E, Papadakis GZ, Keil MF, Lyssikatos C, Carney JA, Arai AE, Lodish M, Stratakis CA. Growth hormone and risk for cardiac tumors in Carney complex. Endocr Relat Cancer 2016; 23:739-46. [PMID: 27535175 PMCID: PMC4991637 DOI: 10.1530/erc-16-0246] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2016] [Accepted: 07/15/2016] [Indexed: 11/08/2022]
Abstract
Carney complex (CNC) is a multiple neoplasia syndrome that is caused mostly by PRKAR1A mutations. Cardiac myxomas are the leading cause of mortality in CNC patients who, in addition, often develop growth hormone (GH) excess. We studied patients with CNC, who were observed for over a period of 20 years (1995-2015) for the development of both GH excess and cardiac myxomas. GH secretion was evaluated by standard testing; dedicated cardiovascular imaging was used to detect cardiac abnormalities. Four excised cardiac myxomas were tested for the expression of insulin-like growth factor-1 (IGF-1). A total of 99 CNC patients (97 with a PRKAR1A mutation) were included in the study with a mean age of 25.8 ± 16.6 years at presentation. Over an observed mean follow-up of 25.8 years, 60% of patients with GH excess (n = 46) developed a cardiac myxoma compared with only 36% of those without GH excess (n = 54) (P = 0.016). Overall, patients with GH excess were also more likely to have a tumor vs those with normal GH secretion (OR: 2.78, 95% CI: 1.23-6.29; P = 0.014). IGF-1 mRNA and protein were higher in CNC myxomas than in normal heart tissue. We conclude that the development of cardiac myxomas in CNC may be associated with increased GH secretion, in a manner analogous to the association between fibrous dysplasia and GH excess in McCune-Albright syndrome, a condition similar to CNC. We speculate that treatment of GH excess in patients with CNC may reduce the likelihood of cardiac myxoma formation and/or recurrence of this tumor.
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Affiliation(s)
- W Patricia Bandettini
- National HeartLung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, Maryland, USA
| | - Alexander S Karageorgiadis
- National Institute of Child Health and Human Development (NICHD)NIH, Bethesda, Maryland, USA Department of PediatricsGeorgetown University Hospital, Washington, District of Columbia, USA
| | - Ninet Sinaii
- Biostatistics and Clinical Epidemiology ServiceClinical Center, NIH, Bethesda, Maryland, USA
| | - Douglas R Rosing
- National HeartLung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, Maryland, USA
| | - Vandana Sachdev
- National HeartLung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, Maryland, USA
| | | | - Evgenia Gourgari
- National Institute of Child Health and Human Development (NICHD)NIH, Bethesda, Maryland, USA Department of PediatricsGeorgetown University Hospital, Washington, District of Columbia, USA
| | - Georgios Z Papadakis
- Department of Radiology and Imaging SciencesClinical Center, NIH, Bethesda, Maryland, USA
| | - Meg F Keil
- National Institute of Child Health and Human Development (NICHD)NIH, Bethesda, Maryland, USA
| | - Charalampos Lyssikatos
- National Institute of Child Health and Human Development (NICHD)NIH, Bethesda, Maryland, USA
| | - J Aidan Carney
- Department of Laboratory Medicine and PathologyMayo Clinic, Rochester, Minnesota, USA
| | - Andrew E Arai
- National HeartLung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, Maryland, USA
| | - Maya Lodish
- National Institute of Child Health and Human Development (NICHD)NIH, Bethesda, Maryland, USA
| | - Constantine A Stratakis
- National Institute of Child Health and Human Development (NICHD)NIH, Bethesda, Maryland, USA
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13
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Shi J, Aronson KJ, Grundy A, Kobayashi LC, Burstyn I, Schuetz JM, Lohrisch CA, SenGupta SK, Lai AS, Brooks-Wilson A, Spinelli JJ, Richardson H. Polymorphisms of Insulin-Like Growth Factor 1 Pathway Genes and Breast Cancer Risk. Front Oncol 2016; 6:136. [PMID: 27376028 PMCID: PMC4896919 DOI: 10.3389/fonc.2016.00136] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2016] [Accepted: 05/23/2016] [Indexed: 12/18/2022] Open
Abstract
Genetic variants of insulin-like growth factor 1 (IGF1) pathway genes have been shown to be associated with breast density and IGF1 levels and, therefore, may also influence breast cancer risk via pro-survival signaling cascades. The aim of this study was to investigate associations between IGF1 pathway single nucleotide polymorphisms (SNPs) and breast cancer risk among European and East Asian women, and potential interactions with menopausal status and breast tumor subtype. Stratified analyses of 1,037 cases and 1,050 controls from a population-based case–control study were conducted to assess associations with breast cancer for 22 SNPs across 5 IGF1 pathway genes in European and East Asian women. Odds ratios were calculated using logistic regression in additive genetic models. Polytomous logistic regression was used to assess heterogeneity by breast tumor subtype. Two SNPs of the IGF1 gene (rs1019731 and rs12821878) were associated with breast cancer risk among European women. Four highly linked IGF1 SNPs (rs2288378, rs17727841, rs7136446, and rs7956547) were modified by menopausal status among East Asian women only and associated with postmenopausal breast cancers. The association between rs2288378 and breast cancer risk was also modified by breast tumor subtype among East Asian women. Several IGF1 polymorphisms were found to be associated with breast cancer risk and some of these associations were modified by menopausal status or breast tumor subtype. Such interactions should be considered when assessing the role of these variants in breast cancer etiology.
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Affiliation(s)
- Joy Shi
- Department of Public Health Sciences, Cancer Research Institute, Queen's University , Kingston, ON , Canada
| | - Kristan J Aronson
- Department of Public Health Sciences, Cancer Research Institute, Queen's University , Kingston, ON , Canada
| | - Anne Grundy
- Individuals and Families, Alberta Cancer Prevention Legacy Fund, Alberta Health Services , Calgary, AB , Canada
| | - Lindsay C Kobayashi
- Department of Epidemiology and Public Health, University College London , London , UK
| | - Igor Burstyn
- Department of Environmental and Occupational Health, Drexel University , Philadelphia, PA , USA
| | - Johanna M Schuetz
- Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency , Vancouver, BC , Canada
| | - Caroline A Lohrisch
- Department of Medical Oncology, British Columbia Cancer Agency , Vancouver, BC , Canada
| | - Sandip K SenGupta
- Department of Pathology and Molecular Medicine, Queen's University , Kingston, ON , Canada
| | - Agnes S Lai
- Department of Cancer Control Research, British Columbia Cancer Agency , Vancouver, BC , Canada
| | - Angela Brooks-Wilson
- Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC, Canada; Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, BC, Canada
| | - John J Spinelli
- Department of Cancer Control Research, British Columbia Cancer Agency, Vancouver, BC, Canada; School of Population and Public Health, University of British Columbia, Vancouver, BC, Canada
| | - Harriet Richardson
- Department of Public Health Sciences, Cancer Research Institute, Queen's University , Kingston, ON , Canada
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Sundström K, Cedervall T, Ohlsson C, Camacho-Hübner C, Sävendahl L. Combined treatment with GH and IGF-I: additive effect on cortical bone mass but not on linear bone growth in female rats. Endocrinology 2014; 155:4798-807. [PMID: 25243853 DOI: 10.1210/en.2014-1160] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
The growth-promoting effect of combined therapy with GH and IGF-I in normal rats is not known. We therefore investigated the efficacy of treatment with recombinant human (rh)GH and/or rhIGF-I on longitudinal bone growth and bone mass in intact, prepubertal, female Sprague-Dawley rats. rhGH was injected twice daily sc (5 mg/kg·d) and rhIGF-I continuously infused sc (2.2 or 4.4 mg/kg·d) for 28 days. Longitudinal bone growth was monitored by weekly x-rays of tibiae and nose-anus length measurements, and tibial growth plate histomorphology was analyzed. Bone mass was evaluated by peripheral quantitative computed tomography. In addition, serum levels of IGF-I, rat GH, acid labile subunit, IGF binding protein-3, 150-kDa ternary complex formation, and markers of bone formation and degradation were measured. Monotherapy with rhGH was more effective than rhIGF-I (4.4 mg/kg·d) to increase tibia and nose-anus length, whereas combined therapy did not further increase tibia, or nose-anus, lengths or growth plate height. In contrast, combined rhGH and rhIGF-I (4.4 mg/kg·d) therapy had an additive stimulatory effect on cortical bone mass vs rhGH alone. Combined treatment with rhGH and rhIGF-I resulted in markedly higher serum IGF-I concentrations vs rhGH alone but did not compromise the endogenous secretion of GH. We conclude that rhIGF-I treatment augments cortical bone mass but does not further improve bone growth in rhGH-treated young, intact, female rats.
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Affiliation(s)
- Katja Sundström
- Pediatric Endocrinology Unit (K.S., T.C., C.C.-H., L.S.), Department of Women's and Children's Health, Karolinska Institutet, SE-17176 Stockholm, Sweden; and Centre for Bone and Arthritis Research (C.O.), Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, SE-41345 Gothenburg, Sweden
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15
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Muc-Wierzgoń M, Nowakowska-Zajdel E, Dzięgielewska-Gęsiak S, Kokot T, Klakla K, Fatyga E, Grochowska-Niedworok E, Waniczek D, Wierzgoń J. Specific metabolic biomarkers as risk and prognostic factors in colorectal cancer. World J Gastroenterol 2014; 20:9759-9774. [PMID: 25110413 PMCID: PMC4123364 DOI: 10.3748/wjg.v20.i29.9759] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2013] [Revised: 11/05/2013] [Accepted: 04/23/2014] [Indexed: 02/06/2023] Open
Abstract
Advances in genomics, molecular pathology and metabolism have generated many candidate biomarkers of colorectal cancer with potential clinical value. Epidemiological and biological studies suggest a role for adiposity, dyslipidaemia, hyperinsulinemia, altered glucose homeostasis, and elevated expression of insulin-like growth factor (IGF) axis members in the risk and prognosis of cancer. This review discusses some recent past and current approaches being taken by researches in obesity and metabolic disorders. The authors describe three main systems as the most studied metabolic candidates of carcinogenesis: dyslipidemias, adipokines and insulin/IGF axis. However, each of these components is unsuccessful in defining the diseases risk and progression, while their co-occurrence increases cancer incidence and mortality in both men and women.
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16
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Ong J, Salomon J, te Morsche RHM, Roelofs HMJ, Witteman BJM, Dura P, Lacko M, Peters WHM. Polymorphisms in the insulin-like growth factor axis are associated with gastrointestinal cancer. PLoS One 2014; 9:e90916. [PMID: 24608110 PMCID: PMC3946608 DOI: 10.1371/journal.pone.0090916] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2013] [Accepted: 02/06/2014] [Indexed: 12/31/2022] Open
Abstract
INTRODUCTION Numerous factors influence the development of gastrointestinal (GI) cancer. The insulin-like growth factor (IGF) axis plays a role in embryonic and postnatal growth and tissue repair. Elevated levels of IGFs, low levels of IGF binding proteins (IGFBPs) and over-expression of IGF receptor (IGFR-I) were associated with several stages of cancer. Here, the prevalence of the single nucleotide polymorphisms (SNPs) rs6214 in the IGF type I (IGF-I) gene and rs6898743 in the growth hormone receptor (GHR) gene in patients with GI cancer and controls was studied. MATERIALS & METHODS In this Dutch case-control study, DNA isolated from blood of 1,457 GI cancer patients; 438 patients with head and neck cancer (HNC), 475 with esophageal cancer (EC) and 544 with colorectal cancer (CRC) and 1,457 matched controls, was used to determine the rs6214 and rs6898743 genotypes by polymerase chain reaction. The association between these SNPs and GI cancer, HNC, esophageal adenocarcinoma (EAC), esophageal squamous-cell carcinoma (ESCC) and proximal or distal CRC was studied. Odds ratios (ORs) with 95% confidence interval (95% CI) were calculated via unconditional logistic regression. RESULTS Overall for GI cancer, the ORs for SNPs rs6214 and rs6898743 were approximately 1.0 (p-value>0.05), using the most common genotypes GG as reference. An OR of 1.54 (95% CI, 1.05-2.27) was found for EC for genotype AA of rs6214. The ORs for EAC were 1.45 (95% CI, 1.04-2.01) and 1.71 (95% CI, 1.10-2.68), for genotypes GA and AA, respectively. Genotype GC of rs6898743 showed an OR of 0.47 (95% CI, 0.26-0.86) for ESCC. CONCLUSION The A allele of SNP rs6214 in the IGF-I gene was associated with EAC, and with HNC in women. The GC genotype of rs6898743 in the GHR gene was negatively associated with ESCC.
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Affiliation(s)
- Jennie Ong
- Department of Gastroenterology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands
| | - Jody Salomon
- Department of Gastroenterology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands
| | - Rene H. M. te Morsche
- Department of Gastroenterology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands
| | - Hennie M. J. Roelofs
- Department of Gastroenterology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands
| | - Ben J. M. Witteman
- Department of Gastroenterology, Hospital Gelderse Vallei, Ede, the Netherlands
| | - Polat Dura
- Department of Gastroenterology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands
| | - Martin Lacko
- Department of Otorhinolaryngology, Head and Neck Surgery, Maastricht University Medical Center, Maastricht, the Netherlands
| | - Wilbert H. M. Peters
- Department of Gastroenterology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands
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17
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Onitilo AA, Engel JM, Glurich I, Stankowski RV, Williams GM, Doi SA. Diabetes and cancer II: role of diabetes medications and influence of shared risk factors. Cancer Causes Control 2012; 23:991-1008. [PMID: 22527174 PMCID: PMC4138811 DOI: 10.1007/s10552-012-9971-4] [Citation(s) in RCA: 68] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2011] [Accepted: 04/14/2012] [Indexed: 12/11/2022]
Abstract
An association between type 2 diabetes mellitus (DM) and cancer has long been postulated, but the biological mechanism responsible for this association has not been defined. In part one of this review, we discussed the epidemiological evidence for increased risk of cancer, decreased cancer survival, and decreased rates of cancer screening in diabetic patients. Here we review the risk factors shared by cancer and DM and how DM medications play a role in altering cancer risk. Hyperinsulinemia stands out as a major factor contributing to the association between DM and cancer, and modulation of circulating insulin levels by DM medications appears to play an important role in altering cancer risk. Drugs that increase circulating insulin, including exogenous insulin, insulin analogs, and insulin secretagogues, are generally associated with an increased cancer risk. In contrast, drugs that regulate insulin signaling without increasing levels, especially metformin, appear to be associated with a decreased cancer risk. In addition to hyperinsulinemia, the effect of DM medications on other shared risk factors including hyperglycemia, obesity, and oxidative stress as well as demographic factors that may influence the use of certain DM drugs in different populations are described. Further elucidation of the mechanisms behind the association between DM, cancer, and the role of DM medications in modulating cancer risk may aid in the development of better prevention and treatment options for both DM and cancer. Additionally, incorporation of DM medication use into cancer prediction models may lead to the development of improved risk assessment tools for diabetic patients.
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Affiliation(s)
- Adedayo A Onitilo
- Department of Hematology/Oncology, Marshfield Clinic Weston Center, WI 54476, USA.
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18
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Kim WY, Kim MJ, Moon H, Yuan P, Kim JS, Woo JK, Zhang G, Suh YA, Feng L, Behrens C, Van Pelt CS, Kang H, Lee JJ, Hong WK, Wistuba II, Lee HY. Differential impacts of insulin-like growth factor-binding protein-3 (IGFBP-3) in epithelial IGF-induced lung cancer development. Endocrinology 2011; 152:2164-73. [PMID: 21447628 PMCID: PMC3100627 DOI: 10.1210/en.2010-0693] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The IGF axis has been implicated in the risk of various cancers. We previously reported a potential role of tissue-derived IGF in lung tumor formation and progression. However, the role of IGF-binding protein (IGFBP)-3, a major IGFBP, on the activity of tissue-driven IGF in lung cancer development is largely unknown. Here, we show that IGF-I, but not IGF-II, protein levels in non-small-cell lung cancer (NSCLC) were significantly higher than those in normal and hyperplastic bronchial epithelium. We found that IGF-I and IGFBP-3 levels in NSCLC tissue specimens were significantly correlated with phosphorylated IGF-IR (pIGF-IR) expression. We investigated the impact of IGFBP-3 expression on the activity of tissue-driven IGF-I in lung cancer development using mice carrying lung-specific human IGF-I transgene (Tg), a germline-null mutation of IGFBP-3, or both. Compared with wild-type (BP3(+/+)) mice, mice carrying heterozygous (BP3(+/-)) or homozygous (BP3(-/-)) deletion of IGFBP-3 alleles exhibited decreases in circulating IGFBP-3 and IGF-I. Unexpectedly, IGF(Tg) mice with 50% of physiological IGFBP-3 (BP3(+/-); IGF(Tg)) showed higher levels of pIGF-IR/IR and a greater degree of spontaneous or tobacco carcinogen [4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone]-induced lung tumor development and progression than did the IGF(Tg) mice with normal (BP3(+/+;) IGF(Tg)) or homozygous deletion of IGFBP-3 (BP3(-/-); IGF(Tg)). These data show that IGF-I is overexpressed in NSCLC, leading to activation of IGF-IR, and that IGFBP-3, depending on its expression level, either inhibits or potentiates IGF-I actions in lung carcinogenesis.
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Affiliation(s)
- Woo-Young Kim
- Department of Thoracic Head, University of Texas M.D. Anderson Cancer Center, TX, USA
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19
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Anthropometric correlates of insulin-like growth factor 1 (IGF-1) and IGF binding protein-3 (IGFBP-3) levels by race/ethnicity and gender. Ann Epidemiol 2010; 19:841-9. [PMID: 19944347 DOI: 10.1016/j.annepidem.2009.08.005] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2009] [Revised: 07/28/2009] [Accepted: 08/12/2009] [Indexed: 11/24/2022]
Abstract
PURPOSE Insulin-like growth factor 1 (IGF-1) levels are positively related to some cancers and negatively related to cardiovascular disease. These conditions are also related to insulin resistance and high body weight, leading to the hypothesis that IGF-1 levels may, in part, mediate the association of high body weight with these health outcomes. Using the National Health and Nutrition Examination Survey (NHANES) III population, we examined the associations between IGF-1, IGF binding protein-3 (IGFBP-3), and the IGF-1/IGFBP-3 molar ratio with anthropometric measures in a large, U.S. population-based study where these associations could also be stratified by race/ethnicity and gender. METHODS The study population consisted of 3,168 women and 2,635 men (44% non-Hispanic white, 28.2% non-Hispanic black, and 27.7% Mexican-American). Anthropometric measures were obtained by trained personnel in the NHANES mobile examination centers. IGF-1 and IGFBP-3 were measured using immunoassays by staff at Diagnostic System Laboratories (DSL) Inc. (Webster, TX). Associations of IGF-1, IGFBP-3, and IGF-1/IGFBP-3 molar ratio with anthropometric variables across race/ethnicity and gender were evaluated by using linear regression modeling. RESULTS Body mass index (BMI) was inversely associated with IGF-1 levels across all of the race/ethnicity and gender subgroups. In contrast, BMI, waist to hip ratio (WHR), and waist circumference were positively associated with IGFBP-3 levels only in non-Hispanic black men and non-Hispanic white women. The IGF-1/IGFBP-3 molar ratio was inversely associated with all anthropometric measures, except height, in all subgroups of the population. CONCLUSION The significant inverse associations of BMI with IGF-1 levels and of all anthropometric variables, except height, with the IGF-1:IGFBP-3 molar ratio in all subgroups do not support existing hypotheses that associations of excess weight with negative health outcomes, such as specific cancer diagnoses, are mediated through high IGF-1 levels.
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20
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Ziemke F, Mantzoros CS. Adiponectin in insulin resistance: lessons from translational research. Am J Clin Nutr 2010; 91:258S-261S. [PMID: 19906806 PMCID: PMC2793112 DOI: 10.3945/ajcn.2009.28449c] [Citation(s) in RCA: 294] [Impact Index Per Article: 19.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Adiponectin is an adipose tissue-secreted endogenous insulin sensitizer, which plays a key role as a mediator of peroxisome proliferator-activated receptor gamma action. Adiponectin alters glucose metabolism and insulin sensitivity, exhibits antiinflammatory and antiatherogenic properties, and has been linked to several malignancies. Circulating concentrations of adiponectin are determined primarily by genetic factors, nutrition, exercise, and abdominal adiposity. Adiponectin concentrations are lower in subjects with obesity, metabolic syndrome, and cardiovascular disease. Adiponectin knockout mice manifest glucose intolerance, insulin resistance, and hyperlipidemia and tend to develop malignancies especially when on high-fat diets. Animal studies have also shown beneficial effects of adiponectin in rodents in vivo. Circulating concentrations of adiponectin are lower in patients with diabetes, cardiovascular disease, and several malignancies. Studies to date provide promising results for the diagnostic and therapeutic role of adiponectin in obesity, insulin resistance, diabetes, cardiovascular disease, and obesity-associated malignancies.
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Affiliation(s)
- Florencia Ziemke
- Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
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21
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Olivo-Marston SE, Hursting SD, Lavigne J, Perkins SN, Maarouf RS, Yakar S, Harris CC. Genetic reduction of circulating insulin-like growth factor-1 inhibits azoxymethane-induced colon tumorigenesis in mice. Mol Carcinog 2009; 48:1071-6. [PMID: 19760669 DOI: 10.1002/mc.20577] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
High levels of insulin-like growth factor-1 (IGF-1) have been associated with a significant increase in colon cancer risk. Additionally, IGF-1 inhibits apoptosis and stimulates proliferation of colonic epithelial cells in vitro. Unfortunately, IGF-1 knockout mice have severe developmental abnormalities and most do not survive, making it difficult to study how genetic ablation of IGF-1 affects colon tumorigenesis. To test the hypothesis that inhibition of IGF-1 prevents colon tumorigenesis, we utilized a preexisting mouse model containing a deletion of the igf1 gene in the liver through a Cre/loxP system. These liver-specific IGF-1 deficient (LID) mice display a 50-75% reduction in circulating IGF-1 levels. We conducted a pilot study to assess the impact of liver-specific IGF-1 deficiency on azoxymethane (AOM)-induced colon tumors. LID mice had a significant inhibition of colon tumor multiplicity in the proximal area of the colon compared to their wild-type littermates. We examined markers of proliferation and apoptosis in the colons of the LID and wild-type mice to see if these were consistent with tumorigenesis. We observed a decrease in proliferation in the colons of the LID mice and an increase in apoptosis. Finally, we examined cytokine levels to determine whether IGF-1 interacts with inflammatory pathways to affect colon tumorigenesis. We observed a significant reduction in the levels of 7 out of 10 cytokines that were measured in the LID mice as compared to wild-type littermates. Results from this pilot study support the hypothesis that reductions in circulating IGF-1 levels may prevent colon tumorigenesis and affect both proliferation and apoptosis. Future experiments will investigate downstream genes of the IGF-1 receptor.
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Affiliation(s)
- Susan E Olivo-Marston
- Laboratory of Human Carcinogenesis, National Cancer Institute, Center for Cancer Research, NIH, Bethesda, Maryland 20892-4258, USA
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22
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Mattsson A, Svensson D, Schuett B, Osterziel KJ, Ranke MB. Multidimensional reference regions for IGF-I, IGFBP-2 and IGFBP-3 concentrations in serum of healthy adults. Growth Horm IGF Res 2008; 18:506-516. [PMID: 18550406 DOI: 10.1016/j.ghir.2008.04.005] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2007] [Revised: 04/03/2008] [Accepted: 04/25/2008] [Indexed: 01/25/2023]
Abstract
CONTEXT The insulin-like growth factor (IGF) system exerts many effects on the growth and differentiation of both normal and malignant cells. The serum concentrations of insulin-like growth factor I (S-IGF-I), insulin-like growth factor-binding protein 2 (S-IGFBP-2) and insulin-like growth factor-binding protein 3 (S-IGFBP-3) and their inter-relations may differ in certain disease states from those seen in healthy individuals. OBJECTIVE To estimate age-, gender- and body mass index (BMI)-specific univariate, bivariate and trivariate 95% reference regions for these components in healthy adults and present indices that will facilitate interpretation of patient observations in relation to these reference regions. DESIGN Blood samples were taken in the morning from 427 healthy, non-fasting German blood donors of both genders (age range, 18-79 years; BMI range, 16-44 kg/m(2)). Reference regions were developed with multivariate regression methods. RESULTS Regression analyses showed that S-IGF-I and S-IGFBP-3 levels decrease with increasing age, whereas S-IGFBP-2 concentrations increase with age (P<0.0001). Females had significantly higher S-IGFBP-3 levels than males (P<0.0001) and similar S-IGF-I and S-IGFBP-2 concentrations. Increasing BMI was associated with decreasing S-IGFBP-2 (P<0.0001), but was not significantly associated with the concentrations of the other two analytes. Controlling for age, gender and BMI, S-IGF-I and S-IGFBP-3 were positively correlated (r=0.58), whereas S-IGF-I and S-IGFBP-2, and S-IGFBP-2 and S-IGFBP-3 were negatively correlated (r=-0.11 and r=-0.18, respectively). Based on the regression models, which were controlled for age, gender and BMI, two- and three-dimensional 95% reference regions with associated patient indices were described for each pair of analytes and for the trio of analytes, respectively. CONCLUSIONS The multivariate reference regions developed in this study should be useful in identifying patients with an abnormal IGF-IGFBP axis. It is suggested that introducing multidimensional reference regions and the described patient indices into clinical practice may aid monitoring of the safety of GH therapy. These patient indices may also be useful in the assessment of cancer risk.
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Affiliation(s)
- Anders Mattsson
- KIMS Medical Outcomes, Pfizer Endocrine Care, Stockholm, Sweden.
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Kaklamani VG, Wisinski KB, Sadim M, Gulden C, Do A, Offit K, Baron JA, Ahsan H, Mantzoros C, Pasche B. Variants of the adiponectin (ADIPOQ) and adiponectin receptor 1 (ADIPOR1) genes and colorectal cancer risk. JAMA 2008; 300:1523-31. [PMID: 18827209 PMCID: PMC2628475 DOI: 10.1001/jama.300.13.1523] [Citation(s) in RCA: 105] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
CONTEXT Current epidemiological evidence suggests an association between obesity, hyperinsulinemia, and colorectal cancer risk. Adiponectin is a hormone secreted by the adipose tissue, and serum levels are inversely correlated with obesity and hyperinsulinemia. While there is evidence of an association between circulating adiponectin levels and colorectal cancer risk, no association between genes of the adiponectin pathway and colorectal cancer have been reported to date. OBJECTIVE To determine the association of 10 haplotype-tagging single-nucleotide polymorphisms (SNPs) of the adiponectin (ADIPOQ) and adiponectin receptor 1 (ADIPOR1) genes with colorectal cancer risk. DESIGN, SETTING, AND PATIENTS Two case-control studies including patients with a diagnosis of colorectal cancer and controls were recruited between 2000 and 2007. Case-control study 1 included a total of 441 patients with a diagnosis of colorectal cancer and 658 controls; both groups were of Ashkenazi Jewish ancestry and from New York, New York. Case-control study 2 included 199 patients with a diagnosis of colorectal cancer and 199 controls from Chicago, Illinois, matched 1:1 for sex, age, and ethnicity. MAIN OUTCOME MEASURES ADIPOQ and ADIPOR1 SNP frequency among cases and controls. RESULTS In study 1, after adjustment for age, sex, and SNPs from the same gene, 3 ADIPOQ SNPs and 1 ADIPOR1 SNP were associated with colorectal cancer risk: rs266729 (adjusted odds ratio [AOR], 0.72; 95% confidence interval [CI], 0.55-0.95) and rs822396 (AOR, 0.37; 95% CI, 0.14-1.00) were associated with decreased risk whereas rs822395 (AOR, 1.76; 95% CI, 1.09-2.84) and rs1342387 (AOR, 1.79; 95% CI, 1.18-2.72) were associated with increased risk. In study 2, after adjustment for age, sex, race, and SNPs from the same gene, the ADIPOQ SNP rs266729 was associated with a decreased colorectal cancer risk of similar magnitude as in study 1 (AOR, 0.52; 95% CI, 0.34-0.78). Combined analysis of both studies shows an association of rs266729 with decreased colorectal cancer risk (AOR, 0.73; 95% CI, 0.53-0.99). CONCLUSION The SNP rs266729, which tags the 5' flanking region of the ADIPOQ gene, is associated with decreased colorectal cancer risk.
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Affiliation(s)
- Virginia G Kaklamani
- Cancer Genetics Program, Division of Hematology and Oncology, Department of Medicine and Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
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24
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Fenton JI, Lavigne JA, Perkins SN, Liu H, Chandramouli GVR, Shih JH, Hord NG, Hursting SD. Microarray analysis reveals that leptin induces autocrine/paracrine cascades to promote survival and proliferation of colon epithelial cells in an Apc genotype-dependent fashion. Mol Carcinog 2008; 47:9-21. [PMID: 17620308 DOI: 10.1002/mc.20357] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The imbalance in systemic mediators of inflammation, such as leptin, is thought to be involved in obesity-associated cancers. In addition, systemic endocrine signals can influence the local autocrine/paracrine factors produced within this microenvironment to influence epithelial cell fate. We previously demonstrated that leptin preferentially promotes the survival and proliferation of colon epithelial cells possessing an Apc mutation (IMCE) but not model normal cells (YAMC). Therefore, the purpose of this study was to identify leptin-induced functional gene family changes which characterize the response of colon epithelial cells possessing an Apc mutation but not normal cells. Consistent with our knowledge of colon carcinogenesis, genes regulating the Wnt/beta-catenin-mediated pathway including Mdm2, Pik3r1, and Rb1 were upregulated by leptin. Importantly, leptin induced IGF-mediated pathway gene expression changes and their protein products in IMCE cells. In the IMCE cells IGFBP-6, IGF-1, and Crim1 expression was upregulated, while IGFBP-2, IGFBP-3, IGFBP-4, IGFBP-5, and Nov expression was downregulated by leptin treatment. These data establish a biologically plausible mechanistic link between the elevated levels of growth factors and the increased risk of colon cancer associated with obesity.
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Affiliation(s)
- Jenifer I Fenton
- Department of Food Science and Human Nutrition, Michigan State University, East Lansing, Michigan, USA
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25
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Ma Z, Dong A, Kong M, Qian J. Silencing of the type 1 insulin-like growth factor receptor increases the sensitivity to apoptosis and inhibits invasion in human lung adenocarcinoma A549 cells. Cell Mol Biol Lett 2007; 12:556-72. [PMID: 17588222 PMCID: PMC6275632 DOI: 10.2478/s11658-007-0022-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2007] [Accepted: 04/02/2007] [Indexed: 12/29/2022] Open
Abstract
The type 1 insulin-like growth factor receptor (IGF-1R), which is over-expressed or activated in many human cancers, including lung cancer, mediates cancer cell proliferation and metastasis. Several studies indicate that blocking IGF-1R expression can inhibit tumor cell proliferation and metastasis. In this study, inhibition of the endogenous IGF-1R by recombinant adenoviruses encoding short hairpin RNAs against IGF-1R was found to significantly suppress IGF-1R expression, arrest the cell cycle, enhance the apoptotic response, and inhibit proliferation, adhesion, invasion and migration in A549 cells. Moreover, silencing IGF-1R decreases the expression of invasive-related genes including matrix metalloproteinase-2 (MMP-2), MMP-9, and urokinase-plasminogen activator (u-PA), and the phosphorylation of Akt and ERK1/2. These results suggest that the silencing of IGF-1R has the potential to be an effective cancer gene therapy strategy for human lung cancer.
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Affiliation(s)
- Zhiyuan Ma
- Department of Cardiothoracic Surgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009 China
- Department of Thoracic and Cardiovascular Surgery, Shanghai Jiao Tong University Affiliated First People’s Hospital, Shanghai, 200080 China
| | - Aiqiang Dong
- Department of Cardiothoracic Surgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009 China
| | - Minjian Kong
- Department of Cardiothoracic Surgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009 China
| | - Jianfang Qian
- Department of Cardiothoracic Surgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009 China
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Quigley CA. Growth hormone treatment of non-growth hormone-deficient growth disorders. Endocrinol Metab Clin North Am 2007; 36:131-86. [PMID: 17336739 DOI: 10.1016/j.ecl.2006.11.006] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Although a large body of data on efficacy and safety of growth hormone (GH) treatment for various non-growth hormone-deficient (GHD) growth disorders has accumulated from a combination of clinical trial and postmarketing sources in the last 20 years or more, there remain limitations. Clinical trial data have the advantage of direct comparison of well-matched, randomized patient groups receiving treatment (or not) under comparable conditions and, as such, provide the highest quality evidence of efficacy. Clinical trials, however, are typically too small for any statistically valid assessment for safety, which is more comprehensively addressed using postmarketing data. Consequently, while the efficacy of GH treatment in children with non-GHD growth disorders has been solidly established and, based on the combination of the rigor of the clinical trial data and numerical power of the postmarketing data, no major concerns exist regarding safety, additional long-term data are required.
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Affiliation(s)
- Charmian A Quigley
- Lilly Research Laboratories, Drop Code 5015, Lilly Corporate Center, Indianapolis, IN 46285, USA.
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27
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Wei EK, Ma J, Pollak MN, Rifai N, Fuchs CS, Hankinson SE, Giovannucci E. C-Peptide, Insulin-like Growth Factor Binding Protein-1, Glycosylated Hemoglobin, and the Risk of Distal Colorectal Adenoma in Women. Cancer Epidemiol Biomarkers Prev 2006; 15:750-5. [PMID: 16614119 DOI: 10.1158/1055-9965.epi-05-0820] [Citation(s) in RCA: 66] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Determinants of insulin secretion and insulin-like growth factors (IGF) have been directly associated with risk for colorectal cancer. However, few studies have evaluated whether these factors are also associated with risk of colorectal adenoma, the main precursor lesion to colorectal cancer. METHODS We identified 380 distal colorectal adenoma cases diagnosed between 1989 and 1998 and 380 controls among nondiabetic women from the cohort of 32,826 women, nested in the Nurses' Health Study, who provided blood samples in 1989 to 1990. Cases and controls were individually matched on year of birth, time period of and indication(s) for endoscopy, and date of blood draw. RESULTS High concentrations of C-peptide, an indicator of insulin secretion, were statistically significantly associated with risk of distal colorectal adenoma [multivariable relative risk (MVRR) top versus bottom quartile, 1.63; 95% confidence interval (95% CI), 1.01-2.66; P = 0.01], even after including body mass index and physical activity in the statistical model. Fasting IGF binding protein-1 (IGFBP-1) concentrations did not show any clear association with risk for adenoma (MVRR top versus bottom quartile, 1.08; 95% CI, 0.56-2.07). These associations did not differ significantly by size/stage of adenoma. Glycosylated hemoglobin (HbA1c) was associated with a nonstatistically significant increased risk of colorectal adenoma (MVRR top versus bottom quartile, 1.47; 95% CI, 0.89-2.44). CONCLUSIONS High HbA1c and low IGFBP-1 were not clearly associated with increased risk of distal colorectal adenoma. However, our current results and previous associations between C-peptide and colorectal cancer suggest that hyperinsulinemia may play a role throughout the development of colorectal neoplasia.
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Affiliation(s)
- Esther K Wei
- Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
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Davies M, Gupta S, Goldspink G, Winslet M. The insulin-like growth factor system and colorectal cancer: clinical and experimental evidence. Int J Colorectal Dis 2006; 21:201-8. [PMID: 15959790 DOI: 10.1007/s00384-005-0776-8] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/05/2005] [Indexed: 02/04/2023]
Abstract
OBJECTIVE The aim of this review is to clarify the involvement of the insulin-like growth factor (IGF) system in the development of colorectal malignancy. MATERIALS AND METHODS Medline searches were used to identify key articles relating the IGF system with the development of colorectal cancer. RESULTS The IGF system has been linked to colorectal malignancy by a convergence of data from epidemiological, clinical and laboratory-based sources. CONCLUSION Further work is needed to characterise the IGF system expression in the colon. Such clarification could lead to the identification of targets that can be manipulated for clinical advantage.
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Affiliation(s)
- M Davies
- University Department of Surgery, Royal Free and University College Medical School, Rowland Hill Street, London, NW3 2PF, UK
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29
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Wei EK, Giovannucci E, Fuchs CS, Willett WC, Mantzoros CS. Low Plasma Adiponectin Levels and Risk of Colorectal Cancer in Men: A Prospective Study. ACTA ACUST UNITED AC 2005; 97:1688-94. [PMID: 16288122 DOI: 10.1093/jnci/dji376] [Citation(s) in RCA: 355] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND Adiponectin is an insulin-sensitizing hormone secreted by adipocytes. Levels of adiponectin are inversely associated with adiposity and insulin resistance. Because both adiposity and insulin resistance have been associated with risk of colorectal cancer, we hypothesized that adiponectin is associated with colorectal carcinogenesis. METHODS We evaluated the association between adiponectin and colorectal cancer among 18 225 men in the Health Professionals Follow-up Study who provided blood samples in 1994. Between blood collection and January 31, 2002, 179 incident colorectal cancer cases occurred. Each case patient was matched to two control subjects on year of birth and date of blood draw. Information on lifestyle factors and diet was collected using biennial questionnaires and food frequency questionnaires. Logistic regression models were used to estimate relative risks (RRs) and confidence intervals (CIs). All statistical tests were two-sided. RESULTS We observed a statistically significant inverse association between plasma adiponectin levels and risk of colorectal cancer (for the highest quintile [Q5] versus the lowest quintile [Q1], RR = 0.42, 95% CI = 0.23 to 0.78; P(trend) = .01). The association was only slightly attenuated after adjustment for body mass index (Q5 versus Q1, RR = 0.48, 95% CI = 0.25 to 0.90; P(trend) = .04) or for body mass index and other major risk factors for colorectal cancer (family history, physical activity, multivitamin use, smoking, alcohol, aspirin use, history of endoscopy, dietary calcium, folate, vitamin E, and vitamin D; Q5 versus Q1, multivariable RR = 0.50, 95% CI = 0.26 to 0.97; P(trend) = .08). Relative risks were not linear in any of the analyses; the second quintile had a lower relative risk than the lowest quintile, but further decreases in risk were not evident with increasing levels of adiponectin. CONCLUSIONS In this prospective nested case-control study, men with low plasma adiponectin levels had a higher risk of colorectal cancer than men with higher levels. More prospective observational studies, particularly in women, and mechanistic studies are required to fully understand the relationship between adiponectin and carcinogenesis.
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Affiliation(s)
- Esther K Wei
- Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School , Boston, MA 02115, USA.
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30
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Wei EK, Ma J, Pollak MN, Rifai N, Fuchs CS, Hankinson SE, Giovannucci E. A prospective study of C-peptide, insulin-like growth factor-I, insulin-like growth factor binding protein-1, and the risk of colorectal cancer in women. Cancer Epidemiol Biomarkers Prev 2005; 14:850-5. [PMID: 15824155 DOI: 10.1158/1055-9965.epi-04-0661] [Citation(s) in RCA: 176] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Hyperinsulinemia, hyperglycemia, and elevated insulin-like growth factor (IGF)-1 levels have been implicated in the etiology of colorectal cancer. However, the joint effects of insulin and IGF-I have not been considered, and whether hyperinsulinemia or hyperglycemia is more etiologically relevant is unclear. IGF binding protein-1 (IGFBP-1) has been hypothesized to mediate the effects of insulin, but epidemiologic data on IGFBP-1 are sparse. We conducted a nested case-control study among the 32,826 women of the Nurses' Health Study who provided a blood sample in 1989 to 1990. After excluding diabetics, we confirmed 182 incident colorectal cancer cases over 10 years of follow-up and 350 controls. Cases were matched to two controls on year of birth, date of blood draw, and fasting status. C-peptide levels were weakly associated with risk of colon cancer [top quartile (Q4) versus bottom quartile (Q1): multivariable relative risk (MVRR), 1.76; 95% confidence interval (95% CI), 0.85-3.63]. Fasting IGFBP-1 was inversely associated with risk of colon cancer (MVRR, 0.28; 95% CI, 0.11-0.75). We observed no clear association between glycosylated hemoglobin and risk for colorectal cancer. The IGF-I to IGFBP-3 molar ratio was associated with colon cancer risk (MVRR, 2.82; 95% CI, 1.35-5.88), and women with low levels of both IGF-I/IGFBP-3 and C-peptide (or high IGFBP-1) were at low risk, and elevation of either was sufficient to increase risk. Although altering IGF-I levels may not be practical, the growing burden of obesity and consequently hyperinsulinemia, which seems increasingly important for colon cancer, may be a target for effective prevention.
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Affiliation(s)
- Esther K Wei
- Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 3rd Floor, 181 Longwood Avenue, Boston, MA 02115, USA.
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Jostel A, Mukherjee A, Hulse PA, Shalet SM. Adult growth hormone replacement therapy and neuroimaging surveillance in brain tumour survivors. Clin Endocrinol (Oxf) 2005; 62:698-705. [PMID: 15943832 DOI: 10.1111/j.1365-2265.2005.02282.x] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
OBJECTIVE Systematic collections of neuroimaging data are nonexistent in brain tumour survivors treated with adult growth hormone replacement therapy (AGHRT). We present our surveillance data. DESIGN In 1993, our unit implemented a policy of performing brain scans on every brain tumour survivor before starting AGHRT, with repeat neuroimaging at least once after 12-18 months' treatment. Reports for baseline scans and most recent scans were analysed for this retrospective study. PATIENTS All brain tumour survivors who received AGHRT (60 patients) were included in the analysis. MEASUREMENTS Evidence and extent of residual tumour, tumour progression, tumour recurrence, and secondary neoplasms (SN) on baseline scan and latest follow-up scan. RESULTS All patients had baseline scans performed. Follow-up scans were available in 41/45 (91%) patients who received AGHRT for more than 1 year (mean duration +/- SD of GHRT was 6.7 +/- 3.6 years). Sixteen patients had residual tumours, and SNs (all meningiomas) were demonstrated in three patients on baseline scans. Appearances remained stable in 34 (83%) patients during follow-up (extending to 17.4 +/- 8.3 years after tumour diagnosis). Of the 16 residual primary tumours, an incurable ependymoma continued to grow, and one meningioma progressed slightly in size over 7.7 years. Follow-up scans also revealed continued growth of the SNs detected at baseline, and five additional meningiomas (two in patients with a previous SN, confirming an excess risk in this subgroup, P = 0.02). All SNs occurred on average 22.8 (range 17-37) years after radiotherapy. CONCLUSIONS Our data do not suggest an increased rate of recurrence or progression of childhood brain tumours during AGHRT. Nonetheless, vigilance and long-term surveillance are needed in these patients in order to detect and monitor SNs, in particular in patients with a previous history of a SN. We endorse a proactive neuroimaging policy, preferably as part of a larger, controlled trial in the future.
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Affiliation(s)
- Andreas Jostel
- Department of Endocrinology, Christie Hospital, Wilmslow Road, Manchester, M20 4BX, UK
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Durai R, Yang W, Gupta S, Seifalian AM, Winslet MC. The role of the insulin-like growth factor system in colorectal cancer: review of current knowledge. Int J Colorectal Dis 2005; 20:203-20. [PMID: 15650828 DOI: 10.1007/s00384-004-0675-4] [Citation(s) in RCA: 88] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/23/2004] [Indexed: 02/04/2023]
Abstract
BACKGROUND The insulin-like growth factor system, which includes insulin-like growth factors (IGF-I and IGF-II), IGF receptors (IGF-IR and IGF-IIR) and IGF binding proteins (IGFBPs), plays an important role in epithelial growth, anti-apoptosis and mitogenesis. There is a growing body of evidence showing that IGFs control growth and proliferation of several types of cancer. This review introduces the latest information on the biology of the IGF system and its pathophysiological role in the development of colorectal cancer. DISCUSSION The growth promoting effects of IGF-I and IGF-II on cancer cells are mediated through the IGF-IR, which is a tyrosine kinase and cancer cells with a strong tendency to metastasise have a higher expression of the IGF-IR. Most of the IGFs in circulation are bound to the IGFBPs, which regulate the bioavailability of the IGFs. All IGFBPs inhibit IGF action by high affinity binding, while some of them also potentiate the effects of IGFs. Colon cancer cells produce specific proteases that degrade the IGFBP so that the IGF will be free to act on the cancer cell in an autocrine manner. Therefore, the IGFBPs play a crucial role in the development of the cancer. CONCLUSION The current knowledge about the link between IGFs and colon cancer is mainly based on in vitro investigations. Further in vivo study is needed to understand the exact role of the IGF system, especially its binding proteins, so that they can be manipulated for the prevention and treatment of colorectal cancer.
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Affiliation(s)
- Rajaraman Durai
- University Department of Surgery, Royal Free and University College Medical School, University College London, Rowland Hill Street, London, NW3 2PF, UK
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Lavigne JA, Baer DJ, Wimbrow HH, Albert PS, Brown ED, Judd JT, Campbell WS, Giffen CA, Dorgan JF, Hartman TJ, Barrett JC, Hursting SD, Taylor PR. Effects of alcohol on insulin-like growth factor I and insulin-like growth factor binding protein 3 in postmenopausal women. Am J Clin Nutr 2005; 81:503-7. [PMID: 15699241 DOI: 10.1093/ajcn.81.2.503] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND Increased circulating insulin-like growth factor I (IGF-I) concentrations, frequently adjusted for IGF binding protein 3 (IGFBP-3), have been associated with increased risk of several types of cancer, including colon, prostate, and breast. Studies have suggested that alcohol may affect IGF-I or IGFBP-3; however, controlled feeding studies to assess alcohol's effects on IGF-I or IGFBP-3 have not been conducted. OBJECTIVE To determine whether chronic, moderate alcohol intake affects serum IGF-I or IGFBP-3 concentrations, we performed a controlled, crossover feeding study. DESIGN Fifty-three postmenopausal women were randomly assigned to consume 0 g (control), 15 g (one drink), or 30 g (2 drinks) alcohol daily for 8 wk and were rotated through the other 2 intake levels in random order. All foods and beverages were provided during the intervention. Individuals were monitored and calories adjusted to maintain constant weight, and serum was collected at the end of each diet period. RESULTS Compared with the effects of 0 g alcohol/d, IGF-I concentrations were nearly unchanged by 15 g alcohol/d (0.8%; 95% CI: -3.2%, 3.5%) but decreased significantly by 4.9% (95% CI: -8.0%, -1.6%) with 30 g alcohol/d. IGFBP-3 concentrations significantly increased by 3.0% (95% CI: 0.4%, 5.6%) with 15 g alcohol/d but did not increase significantly with 30 g/d (1.8%; 95% CI: -0.9%, 4.5%). CONCLUSIONS To our knowledge, this is the first published controlled diet study to find that in postmenopausal women, when weight is kept constant, alcohol consumption reduces the amount of serum IGF-I potentially available for receptor binding. These findings suggest that the effect of alcohol intake should be considered in studies of IGF-I, IGFBP-3, and cancer in postmenopausal women.
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Slattery ML, Murtaugh M, Caan B, Ma KN, Wolff R, Samowitz W. Associations between BMI, energy intake, energy expenditure, VDR genotype and colon and rectal cancers (United States). Cancer Causes Control 2004; 15:863-72. [PMID: 15577288 DOI: 10.1007/s10552-004-1048-6] [Citation(s) in RCA: 54] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Components of energy balance are important elements associated with colorectal cancer risk. In this study we examine the association between VDR genotypes, BMI, physical activity, and energy intake and risk of colorectal cancer. Data from a population-based case-control study of colon (1174 cases and 1174 controls) and rectal (785 cases and 1000 controls) cancer was used to evaluate the associations. The Bsm1, polyA, and Fok1 VDR polymorphisms were evaluated. For colon cancer, those who are obese were at greater risk of colon cancer if they had the SS or BB (OR = 3.50; 95% CI = 1.75-7.03; p interaction 0.03) or ff (OR = 2.62; 95% CI = 1.15-5.99; p interaction 0.12/) VDR genotypes. On the other hand, those who were least physically active were at greater risk of colon cancer if they had the ff VDR genotype (OR = 3.46; 95% CI = 1.58-7.58; p interaction 0.05). The association between energy intake and colon cancer appears to be driven more by energy intake than Bsm1 or polyA VDR genotypes, although there was a significant interaction between the Fok1 VDR polymorphism and energy intake and risk of both colon and rectal cancer (p interaction 0.01 for colon and 0.04 for rectal). These data suggest a relationship between VDR genotype and factors related to energy balance in modifying colorectal cancer risk.
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Affiliation(s)
- Martha L Slattery
- Health Research Center, University of Utah, Salt Lake City, Utah 84108, USA.
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Associations among IRS1, IRS2, IGF1, and IGFBP3 Genetic Polymorphisms and Colorectal Cancer. Cancer Epidemiol Biomarkers Prev 2004. [DOI: 10.1158/1055-9965.1206.13.7] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Abstract
Introduction: Insulin, insulin-like growth factor (IGF), and IGF binding protein (IGFBP) are involved in cell growth and proliferation and are thought to be important in the etiology of colorectal cancer. We hypothesize that genetic polymorphisms of insulin receptor substrates (IRS-1 and IRS-2), IGF-I, and IGFBP-3 alter colorectal cancer risk because of their roles in the insulin-related signaling pathway. Methods: Data from a population-based incident case-control study of 1,346 colon cancer cases and 1,544 population-based controls and 952 rectal cancer cases and 1,205 controls were used to evaluate associations. Genetic polymorphisms of four genes were investigated: an IGF1 CA repeat, the IGFBP3 −202 A > C, the IRS1 G972R, and the IRS2 G1057D. Results: Having at least one R allele (GR or RR) for IRS1 G972R was associated with an increased risk of colon cancer [odds ratio 1.4, 95% confidence interval (95% CI) 1.1-1.9]. The IRS2 G972R heterozygote GD genotype significantly reduced risk of colon cancer (odds ratio 0.8, 95% CI 0.6-0.9). Neither the IGF1 nor the IGFBP3 variants was associated independently with colon cancer, but there was an association when examined with IRS1. Individuals with an IRS1 R allele and IGF1 non-192 allele were at a 2-fold increased risk of colon cancer (95% CI 1.2-4.4). There was a 70% (95% CI 1.02-2.8) increased risk of colon cancer with an IRS1 R allele and the IGFBP3 AC or CC genotype. The IRS2 GD genotype reduced risk of colon cancer, except among those with an IRS1 R allele. No significant associations were seen in analyses of main effects or interactions of these variants and rectal cancer risk. Conclusions: Both IRS1 and IRS2 variants were associated with colon cancer risk independently. Associations were slightly stronger when polymorphisms in multiple genes were evaluated in conjunction with other genes rather than individually. These data suggest that the insulin-related pathway may be important in the etiology of colon cancer but not rectal cancer.
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Slattery ML, Samowitz W, Hoffman M, Ma KN, Levin TR, Neuhausen S. Aspirin, NSAIDs, and Colorectal Cancer: Possible Involvement in an Insulin-Related Pathway. Cancer Epidemiol Biomarkers Prev 2004. [DOI: 10.1158/1055-9965.538.13.4] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Abstract
Introduction: Aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to reduce risk of colorectal cancer. Although inhibition of cyclooxygenase (COX)-2 is generally thought to be the relevant mechanism, aspirin-like drugs apparently are involved in other pathways and mechanisms. We explore the associations between aspirin/NSAIDs, the insulin-related pathway, and the risk of colorectal cancer. Methods: Genetic polymorphisms of five genes identified as being involved in an insulin-related pathway were genotyped using data collected in a case-control study of 1346 incident colon cancer cases and 1544 population-based controls and 952 incident rectal cancer cases and 1205 controls. Genotypes assessed were the 3′ untranslated region poly(A) and the intron 8 BsmI polymorphisms of the VDR gene, a CA repeat polymorphism of the IGF1 gene, the A/C polymorphism at nucleotide −202 of the IGFBP3, the Gly972Arg polymorphism of the IRS1 gene, and the Gly1057Asp polymorphism of the IRS2 gene. Results: Use of aspirin and NSAIDs was associated with a decreased risk of colorectal cancer, with slightly greater protection from NSAIDs than aspirin for rectal cancer. We observed a significant interaction between IRS1 genotype and aspirin/NSAIDs use and risk of colorectal cancer. Relative to the GR/RR IRS1 genotype, a protective effect from the GG IRS1 genotype was seen in those who did not use NSAIDs; use of NSAIDs was protective for all genotypes. These associations were especially strong for those diagnosed prior to age 65 (P interaction = 0.0006). We also observed a significant interaction between aspirin/NSAIDs use and the VDR gene. Having the SS or BB VDR genotypes reduced risk of colorectal cancer among non-aspirin/NSAID users; however, aspirin/NSAIDs reduced risk for all VDR genotypes. Conclusions: These data support the protective effect of aspirin and NSAIDs on colorectal cancer risk. In addition, the observed interactions for aspirin/NSAIDs and IRS1 and VDR genotypes suggest that mechanisms other than COX-2 inhibition may be contributing to the protective effect of aspirin and NSAIDs on colorectal cancer risk.
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Affiliation(s)
| | - Wade Samowitz
- 2Department of Pathology, School of Medicine, University of Utah, Salt Lake City, UT
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Meyerhardt JA, Catalano PJ, Haller DG, Mayer RJ, Benson AB, Macdonald JS, Fuchs CS. Influence of body mass index on outcomes and treatment-related toxicity in patients with colon carcinoma. Cancer 2003; 98:484-95. [PMID: 12879464 DOI: 10.1002/cncr.11544] [Citation(s) in RCA: 249] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
BACKGROUND Obesity is a risk factor for the development of colon carcinoma. The influence of body mass index (BMI) on long-term outcomes and treatment-related toxicity in patients with colon carcinoma has not been well characterized. METHODS This cohort study was conducted within a large, randomized adjuvant chemotherapy trial of 3759 men and women with high-risk, Stage II and Stage III colon carcinoma who were treated between 1988 and 1992 throughout the United States. With a median follow-up of 9.4 years, the authors examined the influence of BMI on disease recurrence, overall survival, and treatment-related toxicity. RESULTS Compared with women of normal weight (BMI, 21.0-24.9 kg/m(2)), obese women with colon carcinoma (BMI > or = 30.0 kg/m(2)) experienced significantly worse overall mortality (hazard ratio [HR], 1.34; 95% confidence interval [95% CI], 1.07-1.67) and a nonsignificant increase in the risk of disease recurrence (HR, 1.24; 95% CI, 0.98-1.59). The influence of BMI among women was not related to any differences in chemotherapy dose-intensity across categories of BMI. In contrast, BMI was not related significantly to long-term outcomes among male patients in this cohort. Among all study participants, obese patients had significantly lower rates of Grade 3-4 leukopenia and lower rates of any Grade > or = 3 toxicity compared with patients of normal weight. CONCLUSIONS Among women with Stage II-III colon carcinoma, obesity was associated with a significant increase in overall mortality as well as a borderline significant increase in disease recurrence. Nonetheless, obesity was not associated with any increase in chemotherapy-related toxicity.
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Weber MM, Fottner C, Liu SB, Jung MC, Engelhardt D, Baretton GB. Overexpression of the insulin-like growth factor I receptor in human colon carcinomas. Cancer 2002; 95:2086-95. [PMID: 12412161 DOI: 10.1002/cncr.10945] [Citation(s) in RCA: 126] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND High concentrations of insulin-like growth factor (IGF)-I and IGF-II have been demonstrated in human colonic adenocarcinomas and exert mitogenic effects through paracrine/autocrine interactions with the IGF-I receptor (IGF-IR). However, definitive studies of IGF-IR expression in these tissues have not been performed. METHODS To study changes in the levels of the IGF-IR in colorectal carcinoma, we analyzed the expression of IGF-IR in 40 paired samples of normal and carcinomatous colonic tissue by quantitative reverse-transcription-polymerase chain reaction (RT-PCR), immunohistochemistry, and ligand binding. RESULTS As measured by RT-PCR, the IGF-IR mRNA ratio in paired tumor and adjacent normal mucosa was higher than 2.0 in 32 of 40 (80%) samples. The overall mean IGF-IR mRNA level was five-fold higher in tumor versus adjacent normal mucosa (P < 0.0001). Overexpression of IGF-IR in colon carcinomas was confirmed at the protein level by immunohistochemistry and receptor-binding studies. Colon carcinoma cells exhibited a positive staining for IGF-IR in 91% of all tumors (30 of 33) whereas the adjacent normal colonic epithelial cells showed only a very faint or no significant IGF-IR immunoreactivity. Radioligand assays and Scatchard analysis in both tissue types revealed a single class of high-affinity IGF-IR-binding sites with a similar dissociation constant (K(d;) 0.14 +/- 0.02 nmol/L, n = 18). However, specific (125)IGF-I-binding and receptor concentrations were elevated in tumor membranes compared with normal mucosa (33.6 +/- 5.6 vs. 22.7 +/- 3.4 fmol/mg protein, P < 0.05). IGF-I affinity crosslinking and sodium dodecyl sulfate-polyacrylamide gel electrophoresis displayed specific bands corresponding to the size of the normal alpha-subunit of the IGF-IR that were more intense in carcinomatous samples. IGF-II mRNA levels were significantly elevated in colorectal carcinomas (P < 0.0001). The IGF-II mRNA ratio in tumor versus normal tissue was elevated more than twofold in 28 of 40 paired samples and a positive correlation was observed between the overexpression of IGF-II and IGF-IR in the tumors. CONCLUSIONS Our results demonstrate that, in addition to IGF-II, a strong overexpression of IGF-IR is found in the majority of colorectal carcinomas, supporting the hypothesis of an important role of the IGF system in the pathogenesis of colorectal carcinoma.
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Affiliation(s)
- Matthias M Weber
- Klinik II und Poliklinik für Innere Medizin der Universität zu Köln und Lehrstuhl II für Innere Medizin, Köln, Germany.
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Giovannucci E. Insulin, insulin-like growth factors and colon cancer: a review of the evidence. J Nutr 2001; 43:189-94. [PMID: 22022297 PMCID: PMC3192881 DOI: 10.4143/crt.2011.43.3.189] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2010] [Accepted: 03/09/2011] [Indexed: 12/27/2022] Open
Abstract
Insulin and insulin-like growth factor (IGF) axes are major determinants of proliferation and apoptosis and thus may influence carcinogenesis. In various animal models, modulation of insulin and IGF-1 levels through various means, including direct infusion, energy excess or restriction, genetically induced obesity, dietary quality including fatty acid and sucrose content, inhibition of normal insulin secretion and pharmacologic inhibition of IGF-1, influences colonic carcinogenesis. Human evidence also associates high levels of insulin and IGF-1 with increased risk of colon cancer. Clinical conditions associated with high levels of insulin (noninsulin-dependent diabetes mellitus and hypertriglyceridemia) and IGF-1 (acromegaly) are related to increased risk of colon cancer, and increased circulating concentrations of insulin and IGF-1 are related to a higher risk of colonic neoplasia. Determinants and markers of hyperinsulinemia (physical inactivity, high body mass index, central adiposity) and high IGF-1 levels (tall stature) are also related to higher risk. Many studies indicate that dietary patterns that stimulate insulin resistance or secretion, including high consumption of sucrose, various sources of starch, a high glycemic index and high saturated fatty acid intake, are associated with a higher risk of colon cancer. Although additional environmental and genetic factors affect colon cancer, the incidence of this malignancy was invariably low before the technological advances that rendered sedentary lifestyles and obesity common, and increased availability of highly processed carbohydrates and saturated fatty acids. Efforts to counter these patterns are likely to have the most potential to reduce colon cancer incidence, as well as cardiovascular disease and diabetes mellitus.
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Affiliation(s)
- E Giovannucci
- Channing Laboratory, Department of Medicine, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA.
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Marek B, Kajdaniuk D, Kos-Kudl&z shtsls;a B, Ostrowska Z, Niedziol&z shtsls;ka D, Janczewska-Kazek E. Acromegaly and the risk of cancer. PATHOPHYSIOLOGY : THE OFFICIAL JOURNAL OF THE INTERNATIONAL SOCIETY FOR PATHOPHYSIOLOGY 2001; 8:69-75. [PMID: 11720801 DOI: 10.1016/s0928-4680(01)00078-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Recent studies suggest that acromegaly might predispose to an increased risk of benign and malignant neoplasms, thus influencing the final outcome of the disease. The exact mechanism of neoplastic events in acromegaly has not been completely clarified. Several studies indicate an autocrine-paracrine role for growth hormone (GH) and insulin-like growth factor-I (IGF-I) in the proliferation of normal and neoplastic cells. The paper reviews the results of molecular, clinical and epidemiological data supporting a role for GH-IGF-I action in colon, prostate, breast and lung carcinogenesis inpatients with acromegaly.
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Affiliation(s)
- Bogdan Marek
- Department of Pathophysiology, Silesian Medical Academy, Pl. Traugutta 2, 41-800, Zabrze, Poland
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