Possible role of nuclear β‐catenin in resistance to preoperative chemoradiotherapy in locally advanced rectal cancer

Takahashi, Hiroyuki; Nakamura, Koushin; Usami, Akane; Tsuruta, Tomoko; Hashimura, Miki; Matsumoto, Toshihide; Saegusa, Makoto

doi:10.1111/his.13227

Cited by 16 publications

(13 citation statements)

References 38 publications

(57 reference statements)

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“…However, several studies reported an association between treatment resistance and the expression of members of the Wnt/β-catenin pathway (45,46). As described above, we previously used pre-therapeutic gene expression profiling of tumor biopsies to demonstrate that TCF7L2 was expressed at higher levels in resistant compared to responsive primary rectal cancers (8).…”

Section: Discussionmentioning

confidence: 99%

Chemoradiotherapy Resistance in Colorectal Cancer Cells is Mediated by Wnt/β-catenin Signaling

Emons

Spitzner

Reineke

et al. 2017

Molecular Cancer Research

114

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Activation of Wnt/β-catenin signaling plays a central role in the development and progression of colorectal cancer (CRC). The Wnt-transcription factor, TCF7L2, is overexpressed in primary rectal cancers that are resistant to chemoradiotherapy (CRT) and TCF7L2 mediates resistance to CRT. However, it is unclear whether the resistance is mediated by a TCF7L2 inherent mechanism or Wnt/β-catenin signaling in general. Here, inhibition of β-catenin by siRNAs or a small molecule inhibitor (XAV-939) resulted in sensitization of CRC cells to CRT. To investigate the potential role of Wnt/β-catenin signaling in controlling therapeutic responsiveness, non-tumorigenic RPE-1 cells were stimulated with Wnt-3a, a physiological ligand of Frizzled-receptors, which increased resistance to CRT. This effect could be recapitulated by overexpression of a degradation-resistant mutant of β-catenin (S33Y), also boosting resistance of RPE-1 cells to CRT, which was, conversely, abrogated by siRNA-mediated silencing of β-catenin. Consistent with these findings, higher expression levels of active β-catenin were observed as well as increased TCF/LEF reporter activity in SW1463 cells that evolved radiation resistance due to repeated radiation treatment. Global gene expression profiling identified several altered pathways, including PPAR signaling and other metabolic pathways, associated with cellular response to radiation. In summary, aberrant activation of Wnt/β-catenin signaling not only regulates the development and progression of colorectal cancer, but also mediates resistance of rectal cancers to chemoradiotherapy. Implications Targeting Wnt/β-catenin signaling or one of the downstream pathways represents a promising strategy to increase response to CRT.

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Section: Discussionmentioning

confidence: 99%

Chemoradiotherapy Resistance in Colorectal Cancer Cells is Mediated by Wnt/β-catenin Signaling

Emons

Spitzner

Reineke

et al. 2017

Molecular Cancer Research

114

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“…Dysregulation of cell stemness phenotype (e.g., β‑catenin and CD133), cell–cell interaction (e.g., CD44 and E‑cadherin), and cell–matrix interaction (e.g., matrix metalloproteinase) as well as of inflammation (e.g., cytotoxic T cells) are essentially involved in tumor budding [ 53 ]. Analysis of these markers in pretreatment (and rarely post-pretreatment) specimens of colorectal cancer suggests that they could be linked to radio-chemoresistance via selective EMT properties [ 24 , 54 , 55 ]. Based on observations of existing precursors, it has been hypothesized that the EMT process is initiated through alterations induced by radiotherapy [ 24 , 56 ].…”

Section: Discussionmentioning

confidence: 99%

The potential predictive value of tumor budding for neoadjuvant chemoradiotherapy response in locally advanced rectal cancer

et al. 2018

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PurposeThis study was conducted to investigate the potential predictive value of tumor budding for neoadjuvant chemoradiotherapy response in locally advanced rectal cancer.Patients and methodsSurgical specimens of 128 ypUICC (Union for International Cancer Control) stage 0–III mid-to-low rectal cancer patients were identified from a prospectively maintained colorectal cancer database and classified into two groups using the 10 high-power field average method: none/mild tumor budding (BD-0) and moderate/severe tumor budding (BD-1). Overall survival, relapse-free survival (RFS), and recurrence estimates were calculated using the Kaplan–Meier method and compared with the log-rank test. For RFS, a multivariable Cox’s proportional hazards regression analysis was performed.ResultsNo (n = 20) or mild (n = 27) tumor budding (BD-0) was identified in 47 (37%) and moderate (n = 52) or severe (n = 29) tumor budding (BD-1) in 81 (63%) surgical specimens. Positive tumor budding (BD-1) was associated with significantly reduced T‑level downstaging (P < 0.001) and tumor regression (P < 0.001). After a median follow-up time of 7 years (range 2.9–146.7 months), BD-0 patients had more favorable 5‑year RFS (90 vs. 71%, P = 0.02) and distant recurrence (2 vs. 12%, P = 0.03) estimates. Multivariable analyses confirmed BD-1 as a negative predictive parameter for RFS (hazard ratio = 3.44, 95% confidence interval 1.23–9.63, P = 0.018).ConclusionsOur data confirm tumor budding as a strong prognostic factor and its potential predictive value for neoadjuvant chemoradiotherapy response in locally advanced rectal cancer patients. This provides the opportunity to modify and individualize neoadjuvant therapy regimens for non-responders.

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“…Suppression of Axin2 by miR-103/107 was demonstrated to enhance CRC chemoresistance by promoting cell stemness via Wnt/β-catenin signaling [49]. Moreover, accumulation of nuclear β-catenin enhances both the chemoresistance and radioresistance of locally advanced rectal cancer through regulating EMT/CSC properties, and nuclear β-catenin in pretreatment-biopsied samples is promising in predicting the efficacy of chemoradiotherapy in rectal cancer patients [50]. Liu et al [51] showed that CD146 decreased the drug resistance of colorectal cancer by functioning as a suppressor of cancer stemness through inactivating the Wnt/β-catenin cascade.…”

Section: Wnt/β-catenin Signaling and Colorectal Cancer Stem Cells In mentioning

confidence: 99%

Role of Wnt/β-Catenin Signaling in the Chemoresistance Modulation of Colorectal Cancer

Yuan

Tao

Zhang

et al. 2020

BioMed Research International

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Colorectal cancer (CRC) is a common malignancy with high morbidity and mortality worldwide. To date, chemotherapy plays an important role in the treatment of CRC patients. Multidrug resistance (MDR) is one of the major hurdles in chemotherapy for CRC, and the underlying mechanisms need to be explored. Studies have demonstrated that Wnt/β-catenin signaling plays a critical role in oncogenesis and tumor development, and its function in inhibiting apoptosis could facilitate tumor chemoresistance. Recent investigations have also suggested the regulatory effects of the Wnt/β-catenin signaling pathway in response to chemotherapeutic agents in CRC. Here, we particularly focus on reviewing the evidences suggesting the mechanisms of Wnt/β-catenin signaling in the chemoresistance modulation of colorectal cancer.

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Possible role of nuclear β‐catenin in resistance to preoperative chemoradiotherapy in locally advanced rectal cancer

Cited by 16 publications

References 38 publications

Chemoradiotherapy Resistance in Colorectal Cancer Cells is Mediated by Wnt/β-catenin Signaling

Chemoradiotherapy Resistance in Colorectal Cancer Cells is Mediated by Wnt/β-catenin Signaling

The potential predictive value of tumor budding for neoadjuvant chemoradiotherapy response in locally advanced rectal cancer

Role of Wnt/β-Catenin Signaling in the Chemoresistance Modulation of Colorectal Cancer

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