Incidence of Diabetes in Colorectal Cancer Survivors

Background:

A higher risk of colorectal cancer (CRC) in patients with diabetes has been well documented. However, little is known regarding diabetes incidence in CRC survivors. This may have substantial impact on CRC survivorship care as well as enhancing the understanding of the interplay between the two diseases. We explored whether the incidence of diabetes was higher among patients with CRC than matched control subjects.

Methods:

Using population-based data from Ontario, Canada, we generated a dataset comprising 39 707 incident CRC cases and 198 535 age- and sex-matched control subjects (1:5) dating from April 2002 to March 2010. We used cause-specific hazard models to estimate the hazard ratios (HRs) for diabetes overall and in subgroups stratified by receipt of systemic chemotherapy, diagnosis of metastatic disease, and site of cancer.

Results:

During a mean follow-up of 4.81 years, the association between CRC and diabetes varied: The rate of developing diabetes was 53% higher among CRC patients compared with control subjects in the first year postdiagnosis (HR = 1.53, 95% confidence interval [CI] = 1.42 to 1.64) and remained increased by 19% in the fifth year postdiagnosis (HR = 1.19, 95% CI = 1.05 to 1.35). Findings were similar in subgroups of patients who had colon cancer, received systemic chemotherapy, or had no evidence of metastasis.

Conclusion:

We found that CRC patients were statistically significantly more likely to develop subsequent diabetes than persons without CRC for up to five years after the diagnosis. Our study suggests that active screening and counseling regarding modifiable risk factors may be warranted in this high-risk group.

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Immunotherapy Combined or Sequenced With Targeted Therapy in the Treatment of Solid Tumors: Current Perspectives

The advent of newer immunotherapeutic and molecularly targeted agents has provided a number of effective options for cancer treatment but has also added much complexity in selecting the best initial treatment or treatment plan for each patient. Molecularly targeted agents offer selectivity and are the cornerstone for "precision medicine." While targeted agents are associated with high tumor response rates, patients inevitably develop resistance to these drugs. Immunotherapies exploit the endogenous immune system to eradicate cancer and can produce durable disease control that results in long-term, treatment-free survival in some patients. Guidelines for treatment selection in patients with specific tumor types and clinical features are routinely being reconsidered in order to accommodate the increasingly complex treatment landscapes. Here, we review current perspectives on the use of immunotherapeutic agents, particularly immune checkpoint inhibitors (nivolumab, pembrolizumab, and ipilimumab), in combination or in sequence with molecularly targeted agents in patients with advanced melanoma as well as other tumor types. We further discuss remaining unmet needs for patient selection and treatment with approved therapies.

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The dual specificity phosphatase 2 gene is hypermethylated in human cancer and regulated by epigenetic mechanisms

Abstract

Background

Dual specificity phosphatases are a class of tumor-associated proteins involved in the negative regulation of the MAP kinase pathway. Downregulation of the dual specificity phosphatase 2 (DUSP2) has been reported in cancer. Epigenetic silencing of tumor suppressor genes by abnormal promoter methylation is a frequent mechanism in oncogenesis. It has been shown that the epigenetic factor CTCF is involved in the regulation of tumor suppressor genes.

Methods

We analyzed the promoter hypermethylation of DUSP2 in human cancer, including primary Merkel cell carcinoma by bisulfite restriction analysis and pyrosequencing. Moreover we analyzed the impact of a DNA methyltransferase inhibitor (5-Aza-dC) and CTCF on the epigenetic regulation of DUSP2 by qRT-PCR, promoter assay, chromatin immuno-precipitation and methylation analysis.

Results

Here we report a significant tumor-specific hypermethylation of DUSP2 in primary Merkel cell carcinoma (p = 0.05). An increase in methylation of DUSP2 was also found in 17 out of 24 (71 %) cancer cell lines, including skin and lung cancer. Treatment of cancer cells with 5-Aza-dC induced DUSP2 expression by its promoter demethylation, Additionally we observed that CTCF induces DUSP2 expression in cell lines that exhibit silencing of DUSP2. This reactivation was accompanied by increased CTCF binding and demethylation of the DUSP2 promoter.

Conclusions

Our data show that aberrant epigenetic inactivation of DUSP2 occurs in carcinogenesis and that CTCF is involved in the epigenetic regulation of DUSP2 expression.

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A joint model for longitudinal and time-to-event data to better assess the specific role of donor and recipient factors on long-term kidney transplantation outcomes

Abstract

In renal transplantation, serum creatinine (SCr) is the main biomarker routinely measured to assess patient's health, with chronic increases being strongly associated with long-term graft failure risk (death with a functioning graft or return to dialysis). Joint modeling may be useful to identify the specific role of risk factors on chronic evolution of kidney transplant recipients: some can be related to the SCr evolution, finally leading to graft failure, whereas others can be associated with graft failure without any modification of SCr. Sample data for 2749 patients transplanted between 2000 and 2013 with a functioning kidney at 1-year post-transplantation were obtained from the DIVAT cohort. A shared random effect joint model for longitudinal SCr values and time to graft failure was performed. We show that graft failure risk depended on both the current value and slope of the SCr. Deceased donor graft patient seemed to have a higher SCr increase, similar to patient with diabetes history, while no significant association of these two features with graft failure risk was found. Patient with a second graft was at higher risk of graft failure, independent of changes in SCr values. Anti-HLA immunization was associated with both processes simultaneously. Joint models for repeated and time-to-event data bring new opportunities to improve the epidemiological knowledge of chronic diseases. For instance in renal transplantation, several features should receive additional attention as we demonstrated their correlation with graft failure risk was independent of the SCr evolution.

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Pluripotency markers are differentially induced by MEK inhibition in thyroid and melanoma BRAFV600E cell lines.

Pluripotency markers are differentially induced by MEK inhibition in thyroid and melanoma BRAFV600E cell lines.

Cancer Biol Ther. 2016 Feb 1;:0

Authors: Dorris ER, Blackshields G, Sommerville G, Alhashemi M, Dias A, McEneaney V, Smyth P, O'Leary JJ, Sheils O

Abstract
Oncogenic mutations in BRAF are common in melanoma and thyroid carcinoma and drive constitutive activation of the MAPK pathway. Molecularly targeted therapies of this pathway improves survival compared to chemotherapy; however, responses tend to be short-lived as resistance invariably occurs. Cell line models of melanoma and thyroid carcinoma, +/- BRAF(V600E) activating mutation, were treated with the MEK inhibitor PD0325901. Treated and naive samples were assayed for expression of key members of the MAPK pathway. Global microRNA expression profiling of naive and resistant cells was performed via next generation sequencingand indicated pluripotency pathways in resistance. Parental cell lines were progressed to holoclones to confirm the miRNA stemness profile. Members of the MIR302/3;73/3;74/5;20 family of embryonic stem cell specific cell cycle regulating (ESCC) microRNAs were identified as differentially expressed between resistant BRAF(V600E) melanoma and thyroid cell lines. Upregulated expression of gene and protein stemness markers, upregulated expression of MAPK pathway genes and downregulation of the ESCC MIR302 cluster in BRAF(V600E) melanoma indicated an increased stem-like phenotype in resistant BRAF(V600E) melanoma. Conversely, downregulated expression of gene and protein stemness markers, downregulated expression of MAPK pathway genes, upregulation of the ESCC MIR520 cluster, reeexpression of cell surface receptors, and induced differentiation-associated morphology in resistant BRAF(V600E) indicate a differentiated phenotype associated with MEK inhibitor resistance in BRAF(V600E) thyroid cells. The differential patterns of resistance observed between BRAF(V600E) melanoma and thyroid cell lines may reflect tissue type or de novo differentiation, but could have significant impact on the response of primary and metastatic cells to MEK inhibitor treatment. This study provides a basis for the investigation of the cellular differentiation/s;elf-renewal access and its role in resistance to MEK inhibition.

PMID: 26828826 [PubMed - as supplied by publisher]

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Resisting Resistance: Establishing new treatment options for CRPC patients.

Resisting Resistance: Establishing new treatment options for CRPC patients.

Cancer Biol Ther. 2016 Jan 30;:0

Authors: Beedie S, Figg WD

Abstract
Overcoming resistance in castrate resistant prostate cancer requires improved understanding of mechanisms by which resistance occurs, as well as new treatment options. A recent study published in Nature (Li et al. 2015) examines the mechanism of abiraterone activity, and reveals the bioactivity of a breakdown product with exciting repercussions for therapy regimes.

PMID: 26828765 [PubMed - as supplied by publisher]

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Identifying Cancer Origin Using Circulating Tumor Cells.

Identifying Cancer Origin Using Circulating Tumor Cells.

Cancer Biol Ther. 2016 Jan 30;:0

Authors: Lu SH, Tsai WS, Chang YH, Chou TY, Pang ST, Lin PH, Tsai CM, Chang YC

Abstract
Circulating tumor cells (CTCs) have become an established clinical evaluation biomarker. CTC count provides a good correlation with the prognosis of cancer patients, but has only been used with known cancer patients, and has been unable to predict the origin of the CTCs. This study demonstrates the analysis of CTCs for the identification of their primary cancer source. 12 mL blood samples were equally dispensed on six CMx chips, microfluidic chips coated with an anti-EpCAM-conjugated supported lipid bilayer, for CTC capture and isolation. Captured CTCs were eluted to an immunofluorescence (IF) staining panel consisting of six groups of antibodies: anti-panCK, anti-CK18, anti-CK7, anti-TTF-1, anti-CK20/anti-CDX2, and anti-PSA/anti-PSMA. Cancer cell lines of lung (H1975), colorectal (DLD-1, HCT-116), and prostate (PC3, DU145, LNCaP) were selected to establish the sensitivity and specificity for distinguishing CTCs from lung, colorectal, and prostate cancer. Spiking experiments performed in 2 mL of culture medium or whole blood proved the CMx platform can enumerate cancer cells of lung, colorectal, and prostate. The IF panel was tested on blood samples from lung cancer patients (n = 3), colorectal cancer patients (n = 5), prostate cancer patients (n = 5), and healthy individuals (n = 12). Peripheral blood samples found panCK(+) and CK18(+) CTCs in lung, colorectal, and prostate cancers. CTCs expressing CK7(+) or TTF-1(+), (CK20/ CDX2)(+), or (PSA/ PSMA)(+) corresponded to lung, colorectal, or prostate cancer, respectively. In conclusion, we have designed an immunofluorescence staining panel to identify CTCs in peripheral blood to correctly identify cancer cell origin.

PMID: 26828696 [PubMed - as supplied by publisher]

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A novel bispecific antibody, BiSS, with potent anti-cancer activities.

A novel bispecific antibody, BiSS, with potent anti-cancer activities.

Cancer Biol Ther. 2016 Feb 1;:0

Authors: Dong B, Zhou C, He P, Li J, Chen S, Miao J, Li Q, Wang Z

Abstract
One of the most active fields in cancer immunotherapy is the study of bispecific antibodies, which engage immune cells to kill cancer cells. However, a variety of issues are associated with most of current bispecific antibody formats. In this study, we present a novel bispecific antibody, BiSS (Bispecific antibody with Single domain, Single domain antibodies), which was constructed by linking two single domain antibodies, anti-CEA and anti-CD16, in tandem. Unlike most other bispecific antibodies, the BiSS antibody can be expressed and purified from E.coli in large quantities. By recruiting natural killer cells (NK cells) to CEA-positive cancer cells, BiSS led to cancer cell death in vitro. In xenograft models, the BiSS protein blocked cancer progression. The data suggested that the single domain-based bispecific antibody BiSS was functional and can be potentially applied to a broad range of immunotherapies.

PMID: 26828900 [PubMed - as supplied by publisher]

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Pluripotency markers are differentially induced by MEK inhibition in thyroid and melanoma BRAFV600E cell lines.

Pluripotency markers are differentially induced by MEK inhibition in thyroid and melanoma BRAFV600E cell lines.

Cancer Biol Ther. 2016 Feb 1;:0

Authors: Dorris ER, Blackshields G, Sommerville G, Alhashemi M, Dias A, McEneaney V, Smyth P, O'Leary JJ, Sheils O

Abstract
Oncogenic mutations in BRAF are common in melanoma and thyroid carcinoma and drive constitutive activation of the MAPK pathway. Molecularly targeted therapies of this pathway improves survival compared to chemotherapy; however, responses tend to be short-lived as resistance invariably occurs. Cell line models of melanoma and thyroid carcinoma, +/- BRAF(V600E) activating mutation, were treated with the MEK inhibitor PD0325901. Treated and naive samples were assayed for expression of key members of the MAPK pathway. Global microRNA expression profiling of naive and resistant cells was performed via next generation sequencingand indicated pluripotency pathways in resistance. Parental cell lines were progressed to holoclones to confirm the miRNA stemness profile. Members of the MIR302/3;73/3;74/5;20 family of embryonic stem cell specific cell cycle regulating (ESCC) microRNAs were identified as differentially expressed between resistant BRAF(V600E) melanoma and thyroid cell lines. Upregulated expression of gene and protein stemness markers, upregulated expression of MAPK pathway genes and downregulation of the ESCC MIR302 cluster in BRAF(V600E) melanoma indicated an increased stem-like phenotype in resistant BRAF(V600E) melanoma. Conversely, downregulated expression of gene and protein stemness markers, downregulated expression of MAPK pathway genes, upregulation of the ESCC MIR520 cluster, reeexpression of cell surface receptors, and induced differentiation-associated morphology in resistant BRAF(V600E) indicate a differentiated phenotype associated with MEK inhibitor resistance in BRAF(V600E) thyroid cells. The differential patterns of resistance observed between BRAF(V600E) melanoma and thyroid cell lines may reflect tissue type or de novo differentiation, but could have significant impact on the response of primary and metastatic cells to MEK inhibitor treatment. This study provides a basis for the investigation of the cellular differentiation/s;elf-renewal access and its role in resistance to MEK inhibition.

PMID: 26828826 [PubMed - as supplied by publisher]

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Resisting Resistance: Establishing new treatment options for CRPC patients.

Resisting Resistance: Establishing new treatment options for CRPC patients.

Cancer Biol Ther. 2016 Jan 30;:0

Authors: Beedie S, Figg WD

Abstract
Overcoming resistance in castrate resistant prostate cancer requires improved understanding of mechanisms by which resistance occurs, as well as new treatment options. A recent study published in Nature (Li et al. 2015) examines the mechanism of abiraterone activity, and reveals the bioactivity of a breakdown product with exciting repercussions for therapy regimes.

PMID: 26828765 [PubMed - as supplied by publisher]

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Identifying Cancer Origin Using Circulating Tumor Cells.

Identifying Cancer Origin Using Circulating Tumor Cells.

Cancer Biol Ther. 2016 Jan 30;:0

Authors: Lu SH, Tsai WS, Chang YH, Chou TY, Pang ST, Lin PH, Tsai CM, Chang YC

Abstract
Circulating tumor cells (CTCs) have become an established clinical evaluation biomarker. CTC count provides a good correlation with the prognosis of cancer patients, but has only been used with known cancer patients, and has been unable to predict the origin of the CTCs. This study demonstrates the analysis of CTCs for the identification of their primary cancer source. 12 mL blood samples were equally dispensed on six CMx chips, microfluidic chips coated with an anti-EpCAM-conjugated supported lipid bilayer, for CTC capture and isolation. Captured CTCs were eluted to an immunofluorescence (IF) staining panel consisting of six groups of antibodies: anti-panCK, anti-CK18, anti-CK7, anti-TTF-1, anti-CK20/anti-CDX2, and anti-PSA/anti-PSMA. Cancer cell lines of lung (H1975), colorectal (DLD-1, HCT-116), and prostate (PC3, DU145, LNCaP) were selected to establish the sensitivity and specificity for distinguishing CTCs from lung, colorectal, and prostate cancer. Spiking experiments performed in 2 mL of culture medium or whole blood proved the CMx platform can enumerate cancer cells of lung, colorectal, and prostate. The IF panel was tested on blood samples from lung cancer patients (n = 3), colorectal cancer patients (n = 5), prostate cancer patients (n = 5), and healthy individuals (n = 12). Peripheral blood samples found panCK(+) and CK18(+) CTCs in lung, colorectal, and prostate cancers. CTCs expressing CK7(+) or TTF-1(+), (CK20/ CDX2)(+), or (PSA/ PSMA)(+) corresponded to lung, colorectal, or prostate cancer, respectively. In conclusion, we have designed an immunofluorescence staining panel to identify CTCs in peripheral blood to correctly identify cancer cell origin.

PMID: 26828696 [PubMed - as supplied by publisher]

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Issue Information

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Erratum

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Cancers, Vol. 8, Pages 20: Conditional Melanoma Cancer Survival in the United States

Beyond relative survival, which indicates the likelihood that patients will not die from causes associated with their cancer, conditional relative survival probabilities provide further useful prognostic information to cancer patients, tailored to the time already survived from diagnosis. This study presents conditional relative survival for melanoma patients in the United States, diagnosed during 2000–2008 and followed through 2012. Analyses are based on 62,803 male and 50,261 female cases in population-based cancer registries in the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute. Five-year relative survival estimates are presented for melanoma patients who have already survived one, two, three, four, or five years after the initial diagnosis. Five- and ten-year relative survival decreases with age, stage at diagnosis, and is lower among males, Blacks, and Hispanics. Five-year conditional relative survival improves with each year already survived. The potential for improvement in five-year conditional relative survival is greatest for older age, males, Blacks, Hispanics, and in later staged cases. For local disease, five-year conditional relative survival was significantly lower in ages greater than 65 years and in Blacks. It was significantly higher in females, non-Hispanics, and married individuals. Age had a greater inverse relationship with five-year survival in later staged disease. A similar result occurred for females and married individuals. In contrast, non-Hispanics had better five-year survival if diagnosed with local or regional disease, but not distant disease.

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Lycopene, tomato products and prostate cancer-specific mortality among men diagnosed with nonmetastatic prostate cancer in the Cancer Prevention Study-II Nutrition Cohort

Abstract

While dietary lycopene and tomato products have been inversely associated with prostate cancer incidence, there is limited evidence for an association between consumption of lycopene and tomato products and prostate-cancer specific mortality (PCSM). We examined the associations of pre- and post-diagnosis dietary lycopene and tomato product intake with PCSM in a large prospective cohort. This analysis included men diagnosed with nonmetastatic prostate cancer between enrollment in the Cancer Prevention Study-II Nutrition Cohort in 1992 or 1993 and June 2011. Pre-diagnosis dietary data, collected at baseline, were available for 8,898 men, of whom 526 died of prostate cancer through 2012. Post-diagnosis dietary data, collected on follow-up surveys in 1999 and/or 2003, were available for 5,643 men, of whom 363 died of prostate cancer through 2012. Cox proportional hazards regression was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for PCSM. Neither pre- nor post-diagnosis dietary lycopene intake was associated with PCSM (4^th vs. 1^st quartile HR=1.00, 95% CI 0.78 − 1.28; HR=1.22, 95% CI 0.91 − 1.64, respectively). Similarly, neither pre- nor post-diagnosis consumption of tomato products was associated with PCSM. Among men with high-risk cancers (T3-T4, or Gleason score 8-10, or nodal involvement), consistently reporting lycopene intake ≥ median on both post-diagnosis surveys was associated with lower PCSM (HR=0.41, 95% CI 0.17 − 0.99, based on 10 PCSM cases consistently ≥ median intake) compared to consistently reporting intake < median. Future studies are needed to confirm the potential inverse association of consistently high lycopene intake with PCSM among men with high-risk prostate cancers. This article is protected by copyright. All rights reserved.

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Reproductive factors, hormone use and gastric cancer risk: The Singapore Chinese Health Study

ABSTRACT

Gastric cancer incidence varies greatly worldwide, but is consistently twice as high in men than in women. The hormone-related factors hypothesized to be associated with lower risk of gastric cancer in women have not been fully explored in populations with a high background risk of gastric cancer. The Singapore Chinese Health Study (SCHS) is a prospective cohort study in which 34,022 of the participants enrolled between 1993 and 1998 were women between 45 and 74 years of age. Information on reproductive histories, hormone replacement therapy (HRT), and oral contraceptive (OC) use were collected through in-person interviews at baseline. As of December 31, 2013, 269 incident gastric cancer cases were identified. Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated to evaluate gastric cancer risk associations. Older age at natural menopause (≥55 versus <45 years: HR=0.50, 95% CI: 0.25-0.99), type of menopause (other versus natural: HR=0.48, 95% CI: 0.27-0.87), and greater years of menstrual cycling (fourth versus first quartile: HR=0.67, 95%CI: 0.46-0.96) were associated with a decreased risk of gastric cancer. Ever use of OCs and HRT were also associated with reduced risk of gastric cancer; the multivariable-adjusted HRs (95% CIs) were 0.40 (0.17-0.90) for use of HRT >3 years and 0.67 (0.47-0.94) for ever use of OCs, compared with never use. Reproductive factors associated with a longer window of fertility and the use of exogenous hormones were shown to reduce gastric cancer development in a cohort of Chinese women with a high background risk of gastric cancer. This article is protected by copyright. All rights reserved.

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Cytotoxic Activity Against Human Neuroblastoma and Melanoma Cells Mediated by IgM Antibodies Derived from Peripheral Blood of Healthy Donors

Abstract

A small percentage of healthy donors identified in the Western population carry antibodies in their peripheral blood which convey cytotoxic activity against certain human melanoma and neuroblastoma cell lines. We measured the cytotoxic activity of sera and plasmas from healthy donors on the human neuroblastoma cell line Kelly and various melanoma cell lines. Antibodies of IgM isotype, presumably belonging to the class of naturally occuring antibodies, exerted cytotoxic activity in a complement-dependent fashion. Apart from complement-dependent tumor cell lysis, we observed C3 opsonization in all tumor cell lines upon treatment with cytotoxic plasmas. Cell lines tested primarily expressed membrane complement regulatory proteins (mCRP) CD46, CD55 and CD59 to various extents. Blocking of mCRPs by monoclonal antibodies enhanced cell lysis and opsonization, though some melanoma cells remained resistant to complement attack. Epitopes recognized by cytotoxic antibodies were represented by gangliosides such as GD2 and GD3, as evidenced by cellular sialidase pretreatment and enhanced expression of distinct gangliosides. It remains to be clarified why only a small fraction of healthy persons carry these anti-tumor cytotoxic antibodies. This article is protected by copyright. All rights reserved.

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Patient-derived xenograft mouse models of pseudomyxoma peritonei recapitulate the human inflammatory tumor microenvironment

Abstract

Pseudomyxoma peritonei (PMP) is a neoplastic syndrome characterized by peritoneal tumor implants with copious mucinous ascites. The standard of care for PMP patients is aggressive cytoreductive surgery performed in conjunction with heated intraperitoneal chemotherapy. Not all patients are candidates for these procedures and a majority of the patients will have recurrent disease. In addition to secreted mucin, inflammation and fibrosis are central to PMP pathogenesis but the molecular processes that regulate tumor-stromal interactions within the peritoneal tumor microenvironment remain largely unknown. This knowledge is critical not only to elucidate PMP pathobiology but also to identify novel targets for therapy. Here, we report the generation of patient-derived xenograft (PDX) mouse models for PMP and assess the ability of these models to replicate the inflammatory peritoneal microenvironment of human PMP patients. PDX mouse models of low- and high-grade PMP were generated and were of a similar histopathology as human PMP. Cytokines previously shown to be elevated in human PMP were also elevated in PDX ascites. Significant differences in IL-6 and IL-8/KC/MIP2 were seen between human and PDX ascites. Interestingly, these cytokines were mostly secreted by mouse-derived, tumor-associated stromal cells rather than by human-derived PMP tumor cells. Our data suggest that the PMP PDX mouse models are especially suited to the study of tumor-stromal interactions that regulate the peritoneal inflammatory environment in PMP as the tumor and stromal cells in these mouse models are of human and murine origins, respectively. These mouse models are therefore, likely to be useful in vivo surrogates for testing and developing novel therapeutic treatment interventions for PMP.

Our studies suggest that the human versus mouse species differences that exist in the patient-derived xenograft (PDX) mouse models can be exploited to investigate tumor-stromal interactions that help sustain the inflammatory tumor microenvironment in pseudomyxoma peritonei (PMP). The similarities in chemokine/cytokine profiles between human and PDX PMP suggest that the reciprocal interactions between tumor and tumor-associated stromal components are also likely to be conserved in these PDX models. Therefore, these models are good surrogates for modeling the PMP tumor microenvironment.

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miR-708/LSD1 axis regulates the proliferation and invasion of breast cancer cells

Abstract

Breast cancer is one of the most common malignant tumors in women worldwide. The microRNAs (miRNAs) are small, noncoding RNAs that regulate various biological processes, including breast cancer. miR-708 played an important role in a variety of cancers. However, its involvement in breast cancer remains largely unclear. In this study, we found that forced the expression of miR-708 in breast cancer cell lines decreased cell proliferation and invasion, whereas inhibition of miR-708 increased cell growth and invasion. miR-708 could directly target the LSD1 3′UTR to downregulate the expression. Further studies suggested that inhibition of LSD1 could phenocopied function of the miR-708 overexpression in MDA-MB-231 cells .Overexpression of LSD1 could counteract the effects of miR-708 on the proliferation and invasion. Taken together, the results indicate that miR-708 may function as a tumor suppressor gene in breast cancer development, and miR-708/LSD1 axis may be a therapeutic intervention in breast cancer in the future.

miR-708 inhibited tumor cell proliferation and invasion. miR-708 inhibited proliferation and invasion by inhibiting LSD1. miR-708/LSD1 axis regulates the proliferation and invasion of breast cancer cells.

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CD47: a potential immunotherapy target for eliminating cancer cells

Abstract

The relationship between the immune system and cancer growth and aggravation has been discussed over a century. A number of molecules have been shown to participate in this process. CD47, a normal universally expressed member of the immunoglobulin superfamily, plays multiple functions in immune system. Researches demonstrated that CD47 was also highly expressed on the surface of tumor cells as well as cancer stem cells (CSCs). Whether the highly expressed CD47 was associated with tumor growth, metastasis, recurrence, or drug resistance has become the hotspot. Besides the roles of CD47 in tumor immunoregulation, the monoclonal antibodies targeting CD47 used in acute myelogenous leukemia (AML) and bladder CSCs were reported, which shed new light on tumor treatment. CSCs have been recognized as the root of tumor drug resistance and recurrence. Whether CD47 on CSCs could serve as a potential target for future anti-cancer treatment forms the focus of our review. Here we highlight the potential roles of CD47 in immune system, and discuss the promising therapeutic application of anti-CD47 antibodies for eliminating tumor cells.

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CD47: a potential immunotherapy target for eliminating cancer cells

Abstract

The relationship between the immune system and cancer growth and aggravation has been discussed over a century. A number of molecules have been shown to participate in this process. CD47, a normal universally expressed member of the immunoglobulin superfamily, plays multiple functions in immune system. Researches demonstrated that CD47 was also highly expressed on the surface of tumor cells as well as cancer stem cells (CSCs). Whether the highly expressed CD47 was associated with tumor growth, metastasis, recurrence, or drug resistance has become the hotspot. Besides the roles of CD47 in tumor immunoregulation, the monoclonal antibodies targeting CD47 used in acute myelogenous leukemia (AML) and bladder CSCs were reported, which shed new light on tumor treatment. CSCs have been recognized as the root of tumor drug resistance and recurrence. Whether CD47 on CSCs could serve as a potential target for future anti-cancer treatment forms the focus of our review. Here we highlight the potential roles of CD47 in immune system, and discuss the promising therapeutic application of anti-CD47 antibodies for eliminating tumor cells.

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US-localized diffuse optical tomography in breast cancer: comparison with pharmacokinetic parameters of DCE-MRI and with pathologic biomarkers

Abstract

Background

To correlate parameters of Ultrasonography-guided Diffuse optical tomography (US-DOT) with pharmacokinetic features of Dynamic contrast-enhanced (DCE)-MRI and pathologic markers of breast cancer.

Methods

Our institutional review board approved this retrospective study and waived the requirement for informed consent. Thirty seven breast cancer patients received US-DOT and DCE-MRI with less than two weeks in between imaging sessions. The maximal total hemoglobin concentration (THC) measured by US-DOT was correlated with DCE-MRI pharmacokinetic parameters, which included K^trans , k_ep and signal enhancement ratio (SER). These imaging parameters were also correlated with the pathologic biomarkers of breast cancer.

Results

The parameters THC and SER showed marginal positive correlation (r = 0.303, p = 0.058). Tumors with high histological grade, negative ER, and higher Ki-67 expression ≥20 % showed statistically higher THC values compared to their counterparts (p = 0.019, 0.041, and 0.023 respectively). Triple-negative (TN) breast cancers showed statistically higher K^trans values than non-TN cancers (p = 0.048).

Conclusion

THC obtained from US-DOT and K^trans obtained from DCE-MRI were associated with biomarkers indicative of a higher aggressiveness in breast cancer. Although US-DOT and DCE-MRI both measured the vascular properties of breast cancer, parameters from the two imaging modalities showed a weak association presumably due to their different contrast mechanisms and depth sensitivities.

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Low oxygen tension reverses antineoplastic effect of iron chelator deferasirox in human glioblastoma cells

Abstract

Background

Overcoming resistance to treatment is an essential issue in many cancers including glioblastoma (GBM), the deadliest primary tumor of the central nervous system. As dependence on iron is a key feature of tumor cells, using chelators to reduce iron represents an opportunity to improve conventional GBM therapies. The aim of the present study was, therefore, to investigate the cytostatic and cytotoxic impact of the new iron chelator deferasirox (DFX) on human GBM cells in well-defined clinical situations represented by radiation therapy and mild-hypoxia.

Results

Under experimental normoxic condition (21 % O₂), deferasirox (DFX) used at 10 μM for 3 days reduced proliferation, led cell cycle arrest in S and G2-M phases and induced cytotoxicity and apoptosis in U251 and U87 GBM cells. The abolition of the antineoplastic DFX effects when cells were co-treated with ferric ammonium sulfate supports the hypothesis that its effects result from its ability to chelate iron. As radiotherapy is the main treatment for GBM, the combination of DFX and X-ray beam irradiation was also investigated. Irradiation at a dose of 16 Gy repressed proliferation, cytotoxicity and apoptosis, but only in U251 cells, while no synergy with DFX was observed in either cell line. Importantly, when the same experiment was conducted in mild-hypoxic conditions (3 % O₂), the antiproliferative and cytotoxic effects of DFX were abolished, and its ability to deplete iron was also impaired.

Conclusions

Taken together, these in vitro results could raise the question of the benefit of using iron chelators in their native forms under the hypoxic conditions often encountered in solid tumors such as GBM. Developing new chemistry or a new drug delivery system that would keep DFX active in hypoxic cells may be the next step toward their application.

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Cancer survival in New South Wales, Australia: socioeconomic disparities remain despite overall improvements

Abstract

Background

Disparities in cancer survival by socioeconomic status have been reported previously in Australia. We investigated whether those disparities have changed over time.

Methods

We used population-based cancer registry data for 377,493 patients diagnosed with one of 10 major cancers in New South Wales (NSW), Australia. Patients were assigned to an area-based measure of socioeconomic status. Five-year relative survival was estimated for each socioeconomic quintile in each 'at risk' period (1996–2000 and 2004–2008) for the 10 individual cancers. Poisson-regression modelling was used to adjust for several prognostic factors. The relative excess risk of death by socioeconomic quintile derived from this modelling was compared over time.

Results

Although survival increased over time for most individual cancers, Poisson-regression models indicated that socioeconomic disparities continued to exist in the recent period. Significant socioeconomic disparities were observed for stomach, colorectal, liver, lung, breast and prostate cancer in 1996–2000 and remained so for 2004–2008, while significant disparities emerged for cervical and uterus cancer in 2004–2008 (although the interaction between period and socioeconomic status was not significant). About 13.4 % of deaths attributable to a diagnosis of cancer could have been postponed if this socioeconomic disparity was eliminated.

Conclusion

While recent health and social policies in NSW have accompanied an increase in cancer survival overall, they have not been associated with a reduction in socioeconomic inequalities.

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Centrosome amplification induces high grade features and is prognostic of worse outcomes in breast cancer

Abstract

Background

Centrosome amplification (CA) has been reported in nearly all types of human cancer and is associated with deleterious clinical factors such as higher grade and stage. However, previous reports have not shown how CA affects cellular differentiation and clinical outcomes in breast cancer.

Methods

We analyzed centrosomes by immunofluorescence and compared to ploidy and chromosomal instability (CIN) as assessed by 6-chromosome FISH in a cohort of 362 breast cancers with median clinical follow-up of 8.4 years. Centrosomes were recognized by immunofluorescence using antibodies for pericentriolar material (PCM; pericentrin) and centrioles (polyglutamylated tubulin). CA was experimentally induced in cell culture by overexpression of polo-like kinase 4 (PLK4).

Results

CA is associated with reduced all-cause and breast cancer-specific overall survival and recurrence-free survival. CA correlates strongly with high-risk subtypes (e.g. triple negative) and higher stage and grade, and the prognostic nature of CA can be explained largely by these factors. A strong correlation between CA and high tumor ploidy demonstrates that chromosome and centrosome doubling often occur in concert. CA is proposed to be a method of inducing CIN via aberrant mitotic cell divisions; consonant with this, we observed a strong correlation between CA and CIN in breast cancers. However, some CA tumors had low levels of CIN, indicating that protective mechanisms are at play, such as centrosome clustering during mitosis. Intriguingly, some high-risk tumors have more acentriolar centrosomes, suggesting PCM fragmentation as another mechanism of CA. In vitro induction of CA in two non-transformed human cell lines (MCF10A and RPE) demonstrated that CA induces a de-differentiated cellular state and features of high-grade malignancy, supporting the idea that CA intrinsically causes high-grade tumors.

Conclusions

CA is associated with deleterious clinical factors and outcomes in breast cancer. Cell doubling events are the most prevalent causes of CA in cancer, although PCM fragmentation may be a secondary cause. CA promotes high-risk breast cancer in part by inducing high-grade features. These findings highlight the importance of centrosome aberrations in the biology of human breast cancer.

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