Anti-metastatic Treatment in Colorectal Cancer: Targeting Signaling Pathways

Lemos, Clara; Sack, Ulrike; Schmid, Felicitas; Juneja, Manisha; Stein, Ulrike

doi:10.2174/138161213804547277

Cited by 13 publications

(12 citation statements)

References 236 publications

(271 reference statements)

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“…Moreover, progression to metastatic disease affects a large number of cases and it represents the subgroup of patients with the worst prognosis. Despite progressive clinical advances that have been carried out in the last decade to decrease or prevent metastasis, patient outcomes are still very poor (2). It is therefore a clinical challenge to develop alternative therapeutic strategies to improve the survival of these patients.…”

Section: Introductionmentioning

confidence: 99%

Deregulation of the PP2A Inhibitor SET Shows Promising Therapeutic Implications and Determines Poor Clinical Outcome in Patients with Metastatic Colorectal Cancer

Cristóbal

Rincón

Manso

et al. 2015

Clinical Cancer Research

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Purpose: SET is an endogenous PP2A inhibitor that might represent a novel molecular target for antitumor therapy. The aim of this study was to evaluate the molecular effects of SET deregulation and its potential clinical significance in metastatic colorectal cancer (mCRC).Experimental Design: We studied the biologic effects of SET on cell growth, colonosphere formation, caspase activity, PP2A activation status, and sensitivity to oxaliplatin and FTY720 treatments. Moreover, we analyzed SET expression by immunostaining in 242 patients with mCRC.Results: SET deregulation promotes cell growth and colonosphere formation and inhibits PP2A, thereby impairing its antitumor effects. Moreover, SET reduces sensitivity to oxaliplatin in colorectal cancer cell lines, which is restored after FTY720 treatment. SET overexpression was detected in 24.8% (60 of 242) of patients with mCRC and determined significantly shorter overall (8.6 vs. 27 months; P < 0.001) and progression-free survival (7.1 vs. 13.7 months; P < 0.001), and poor response to oxaliplatin-based chemotherapy (P ¼ 0.004). Interestingly, its prognostic value was particularly evident in patients younger than 70 years and in those harboring KRAS mutations.Conclusions: SET overexpression is a frequent event in mCRC that plays a potential oncogenic role associated with worse outcome and resistance to oxaliplatin. Moreover, this alteration defines a subgroup of patients who could benefit from therapies containing PP2A activators such as FTY720.

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Section: Introductionmentioning

confidence: 99%

Deregulation of the PP2A Inhibitor SET Shows Promising Therapeutic Implications and Determines Poor Clinical Outcome in Patients with Metastatic Colorectal Cancer

Cristóbal

Rincón

Manso

et al. 2015

Clinical Cancer Research

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“…Their expression in primary tumors was associated with colorectal cancer metastasis and has been used to evaluate prognosis and metastasis of colorectal cancer2-4,6,12-18. At the treatment levels, the inhibitors of HGF/Met are being developed to be novel targeted drugs19,20 for controlling colorectal cancer metastasis8,21.…”

Section: Introductionmentioning

confidence: 99%

Expression of HGF and Met in Human Tissues of Colorectal Cancers: Biological and Clinical Implications for Synchronous Liver Metastasis

Sun¹,

Liu²,

Ma³

et al. 2013

Int. J. Med. Sci.

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Background and aims: Synchronous liver metastasis (SLM) remains a significant problem in newly diagnosed colorectal cancer (CRC). The system of hepatocyte growth factor (HGF) and Met plays an important role in cancer invasion and metastasis and is being developed to be targeted drugs. We aimed to investigate the role of HGF/Met in SLM based on a case-matched study and comparison between primary tumors and matched metastases.Methods: A group of 30 patients with SLM and other two groups of patients without SLM in a hospital database were collected. They were matched into according to clinicopathological factors. 81 patients were included in the study. Their tissues of primary colorectal cancers, lymph nodes and liver metastases were collected to detect HGF and Met expression by immunohistochemistry and RT-PCR.Results: Expression of HGF and Met at the protein level and the RNA level in primary CRCs with SLM were significantly higher than that in primary colorectal carcinomas without liver metastases (all P value<0.05). Their expression was only related to SLM when concurrent with regional lymph node metastasis (all P value<0.05) but had little influence on SLM without involvement of lymph node metastasis (all P value>0.05). Comparison their expression between primary tumors and matched metastases, major concordance and minor difference existed.Conclusions: HGF and Met may exert functions in the development of SLM when concurrent with lymph node metastases but had little influence on SLM without lymph node metastasis, further indicating their roles and potential values for a subtype of colorectal cancer metastasis. Major concordance and minor difference exist between primary tumors and matched metastases, which further provides evidence for evaluating the response to their inhibitors based on primary tumors or metastases.

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“…The other variable, HGF (hepatocyte growth factor) index, represents a pathway that is known to be activated in aggressive CRC. HGF has been extensively investigated as a potential new target (reviewed in [27]). Although HGF expression in immunoperoxidase staining appears with a clear cytoplasmic pattern in CRC cancer cells [28], our immunofluorescence assay demonstrated a nuclear pattern that was of clinical significance.…”

Section: Discussionmentioning

confidence: 99%

Integrated Multidimensional Analysis Is Required for Accurate Prognostic Biomarkers in Colorectal Cancer

Mariani

He²,

McHugh³

et al. 2014

PLoS ONE

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CRC cancer is one of the deadliest diseases in Western countries. In order to develop prognostic biomarkers for CRC (colorectal cancer) aggressiveness, we analyzed retrospectively 267 CRC patients via a novel, multidimensional biomarker platform. Using nanofluidic technology for qPCR analysis and quantitative fluorescent immunohistochemistry for protein analysis, we assessed 33 microRNAs, 124 mRNAs and 9 protein antigens. Analysis was conducted in each single dimension (microRNA, gene or protein) using both the multivariate Cox model and Kaplan-Meier method. Thereafter, we simplified the censored survival data into binary response data (aggressive vs. non aggressive cancer). Subsequently, we integrated the data into a diagnostic score using sliced inverse regression for sufficient dimension reduction. Accuracy was assessed using area under the receiver operating characteristic curve (AUC). Single dimension analysis led to the discovery of individual factors that were significant predictors of outcome. These included seven specific microRNAs, four genes, and one protein. When these factors were quantified individually as predictors of aggressive disease, the highest demonstrable area under the curve (AUC) was 0.68. By contrast, when all results from single dimensions were combined into integrated biomarkers, AUCs were dramatically increased with values approaching and even exceeding 0.9. Single dimension analysis generates statistically significant predictors, but their predictive strengths are suboptimal for clinical utility. A novel, multidimensional integrated approach overcomes these deficiencies. Newly derived integrated biomarkers have the potential to meaningfully guide the selection of therapeutic strategies for individual patients while elucidating molecular mechanisms driving disease progression.

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Anti-metastatic Treatment in Colorectal Cancer: Targeting Signaling Pathways

Cited by 13 publications

References 236 publications

Deregulation of the PP2A Inhibitor SET Shows Promising Therapeutic Implications and Determines Poor Clinical Outcome in Patients with Metastatic Colorectal Cancer

Deregulation of the PP2A Inhibitor SET Shows Promising Therapeutic Implications and Determines Poor Clinical Outcome in Patients with Metastatic Colorectal Cancer

Expression of HGF and Met in Human Tissues of Colorectal Cancers: Biological and Clinical Implications for Synchronous Liver Metastasis

Integrated Multidimensional Analysis Is Required for Accurate Prognostic Biomarkers in Colorectal Cancer

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