BCL-2 family deregulation in colorectal cancer: potential for BH3 mimetics in therapy

Ramesh, Prashanthi; Medema, Jan Paul

doi:10.1007/s10495-020-01601-9

Cited by 80 publications

(67 citation statements)

References 164 publications

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“…The long isoform is preferentially expressed over the shorter isoform when the BCL2L1 gene is induced in neoplastic cells (18). An increased Bcl-xL to Bcl-xS ratio contributes to mitochondrial outer membrane potential maintenance and prevents cytochrome c from spilling into the cytoplasm and from activating caspases, the executioners of apoptosis enzymes (19).…”

Section: Discussionmentioning

confidence: 99%

Chromosome 20q11.21 Amplifications in Colorectal Cancer

Voutsadakis

2021

Cancer Genomics Proteomics

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Background: Colorectal cancer is the most common gastrointestinal carcinoma in western countries. Prognosis of metastatic colorectal cancer has improved in the last decades, but the disease continues to carry an adverse outcome in most cases. An improved understanding of molecular pathogenesis has provided incremental benefits in survival outcomes with the introduction of targeted therapies for specific sub-types and gives hope for further improvements. Materials and Methods: Publicly available data from genomic series of colorectal cancer published by the TCGA were analyzed with the aim of characterizing the sub-set of colorectal cancers carrying amplifications of chromosome 20q11.21, compared with cancers with no amplifications in this locus. Associations of 20q11.21-amplified cancers with other molecular lesions commonly observed in colorectal cancer were explored. mRNA expression of genes from the locus in amplified cases was analyzed. An exploratory survival analysis was also performed. Results: Amplifications of genes at chromosome arm 20q are observed in 7% to 9% of colorectal cancers, representing the most commonly amplified loci in this type of cancer. The 20q11.21 presents the highest amplification rate in the 20q arm. 20q11.21 amplified cancers display concomitant mutations in the KRAS pathway and SMAD4 less often than non-amplified cancers. Mutations in DNA repair genes are also less often encountered in 20q11.21 amplified colorectal cancers than non-amplified ones. Conclusion: Amplification of genes at locus 20q11.21, representing the most frequently amplified locus in colorectal cancers, is associated with specific molecular characteristics and may have therapeutic implications.

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Section: Discussionmentioning

confidence: 99%

Chromosome 20q11.21 Amplifications in Colorectal Cancer

Voutsadakis

2021

Cancer Genomics Proteomics

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“…Dysregulation of BCL-2 proteins occurs during tumor development and is responsible for cellular resistance to chemotherapy treatments [ 53 ]. BCL-2 family proteins are described based on their pro-apoptotic or anti-apoptotic function [ 40 ]. Early immunohistochemical analysis of mucinous and non-mucinous CRCs by Zhang et al demonstrated no association between mucinous histology and BCL-2 staining [ 41 ].…”

Section: Apoptosis and Other Cell Death Signaling Pathways In Mucimentioning

confidence: 99%

Resistance to Cell Death in Mucinous Colorectal Cancer—A Review

OʼConnell

Reynolds

McNamara

et al. 2021

Cancers

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Mucinous colorectal cancer (CRC) is estimated to occur in approximately 10–15% of CRC cases and is characterized by abundant extracellular mucin. Mucinous CRC is frequently associated with resistance to apoptosis. Inferior prognosis is observed in mucinous CRC, particularly in rectal cancer and metastatic cases. Mucins are heavily glycosylated secretory or transmembrane proteins that participate in protection of the colonic epithelium. MUC2 overexpression is a hallmark of mucinous CRCs. Mucinous CRC is associated with KRAS and BRAF mutation, microsatellite instability and the CpG island methylator phenotype. Mutations of the APC gene and p53 mutations which are characteristic non-mucinous colorectal adenocarcinoma are less common in mucinous CRC. Both physical and anti-apoptotic properties of mucin provide mechanisms for resistance to cell death. Mucin glycoproteins are associated with decreased expression of pro-apoptotic proteins, increased expression of anti-apoptotic proteins and increased cell survival signaling. The role for BCL-2 proteins, including BCL-XL, in preventing apoptosis in mucinous CRC has been explored to a limited extent. Additional mechanisms opposing cell death include altered death receptor expression and altered mutation rates in genes responsible for chemotherapy resistance. The roles of alternate cell death programs including necroptosis and pyroptosis are not well understood in mucinous CRC. While the presence of MUC2 is associated with an immunosuppressive environment, the tumor immune environment of mucinous CRC and the role of immune-mediated tumor cell death likewise require further investigation. Improved understanding of cell death mechanisms in mucinous CRC may allow modification of currently used regimens and facilitate targeted treatment.

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“…Bcl-2 is an anti-apoptotic protein that is closely associated with the occurrence of several cancers. BH3 mimics can specifically inhibit the expression of Bcl-2, and change the imbalance of apoptosis of CRC cells 57 ( Figure 3).…”

Section: Targets Of Pssmentioning

confidence: 99%

“… Signaling pathway of BCL-2. Under the pressure, the expression of BH3 increased, which further blocked the expression of Bcl-2, inactivated Bax/Bak, and resulted in the closure of MOMP and apoptosis 57 …”

Section: Figurementioning

confidence: 99%

Application of phototherapeutic-based nanoparticles in colorectal cancer

Yan¹,

Wang²,

Jiang³

et al. 2021

Int. J. Biol. Sci.

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Colorectal cancer (CRC) is the third most commonly diagnosed malignancy and the second leading cause of cancer death, which accounts for approximately 10% of all new cancer cases worldwide. Surgery is the main method for treatment of early-stage CRC. However, it is not effective for most metastatic tumors, and new treatment and diagnosis strategies need to be developed. Photosensitizers (PSs) play an important role in the treatment of CRC. Phototherapy also has a broad prospect in the treatment of CRC because of its low invasiveness and low toxicity. However, most PSs are associated with limitations including poor solubility, poor selectivity and high toxicity. The application of nanomaterials in PSs has added many advantages, including increased solubility, bioavailability, targeting, stability and low toxicity. In this review, based on phototherapy, we discuss the characteristics and development progress of PSs, the targeting of PSs at organ, cell and molecular levels, and the current methods of optimizing PSs, especially the application of nanoparticles as carriers in CRC. We introduce the photosensitizer (PS) targeting process in photodynamic therapy (PDT), the damage mechanism of PDT, and the application of classic PS in CRC. The action process and damage mechanism of photothermal therapy (PTT) and the types of ablation agents. In addition, we present the imaging examination and the application of PDT / PTT in tumor, including (fluorescence imaging, photoacoustic imaging, nuclear magnetic resonance imaging, nuclear imaging) to provide the basis for the early diagnosis of CRC. Notably, single phototherapy has several limitations in vivo , especially for deep tumors. Here, we discuss the advantages of the combination therapy of PDT and PTT compared with the single therapy. At the same time, this review summarizes the clinical application of PS in CRC. Although a variety of nanomaterials are in the research and development stage, few of them are actually on the market, they will show great advantages in the treatment of CRC in the near future.

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BCL-2 family deregulation in colorectal cancer: potential for BH3 mimetics in therapy

Cited by 80 publications

References 164 publications

Chromosome 20q11.21 Amplifications in Colorectal Cancer

Chromosome 20q11.21 Amplifications in Colorectal Cancer

Resistance to Cell Death in Mucinous Colorectal Cancer—A Review

Application of phototherapeutic-based nanoparticles in colorectal cancer

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