Standards and Challenges of Care for Colorectal Cancer Today

Werner, J. A.

doi:10.1159/000447070

Cited by 15 publications

(14 citation statements)

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“…The most common sites of CRC metastases include the liver, lungs, and peritoneum (peritoneal carcinomatosis). While surgery and radiation remain curative options for patients with localized disease, the standard of care for CRC patients with advanced metastatic disease is commonly combination front-line chemotherapy treatment ( Werner and Heinemann, 2016 ). These chemotherapy regimens typically include fluorouracil (5-FU) and leucovorin (LV) in combination, which work together to inhibit DNA and RNA synthesis and modulate tumor growth, extending median survival in patients from 9 months (with palliative care) to over 12 months ( Rodriguez-Bigas et al, 2003 ).…”

Section: Introductionmentioning

confidence: 99%

Oxaliplatin resistance in colorectal cancer enhances TRAIL sensitivity via death receptor 4 upregulation and lipid raft localization

Greenlee

Lopez-Cavestany

Ortiz-Otero

et al. 2021

eLife

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Colorectal cancer (CRC) remains a leading cause of cancer death, and its mortality is associated with metastasis and chemoresistance. We demonstrate that oxaliplatin-resistant CRC cells are sensitized to TRAIL-mediated apoptosis. Oxaliplatin-resistant cells exhibited transcriptional downregulation of caspase-10, but this had minimal effects on TRAIL sensitivity following CRISPR-Cas9 deletion of caspase-10 in parental cells. Sensitization effects in oxaliplatin-resistant cells were found to be a result of increased DR4, as well as significantly enhanced DR4 palmitoylation and translocation into lipid rafts. Raft perturbation via nystatin and resveratrol significantly altered DR4/raft colocalization and TRAIL sensitivity. Blood samples from metastatic CRC patients were treated with TRAIL liposomes, and a 57% reduction of viable circulating tumor cells (CTCs) was observed. Increased DR4/lipid raft colocalization in CTCs was found to correspond with increased oxaliplatin resistance and increased efficacy of TRAIL liposomes. To our knowledge, this is the first study to investigate the role of lipid rafts in primary CTCs.

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Section: Introductionmentioning

confidence: 99%

Oxaliplatin resistance in colorectal cancer enhances TRAIL sensitivity via death receptor 4 upregulation and lipid raft localization

Greenlee

Lopez-Cavestany

Ortiz-Otero

et al. 2021

eLife

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“…More than 70% of CRC-related deaths are caused by metastases to the liver (Neo et al, 2010). The first line treatment for early-stage colon cancer is surgical resection, which may be preceded (neoadjuvant) or followed by (adjuvant) chemotherapy for later stage disease (Braun et al, 2011;Werner et al, 2016). Chemotherapeutic options usually involve combinations of oxaliplatin (OX), 5-fluorouracil (5-FU), leucovorin/folinic acid (FA), and irinotecan (IR) -these combinations are offered as FOLFOX (OX, 5-FU and FA), FOLFIRI (IR,, or FOLFOXIRI (all four) (Braun et al, 2011;Goldberg et al, 2004;A.…”

Section: Colorectal Cancer Incidence Treatment and Mortalitymentioning

confidence: 99%

Characterisation of cancer stem cells and the renin-angiotensin system in colon adenocarcinoma

Munro¹

2021

Preprint

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Colorectal cancer (CRC) is the third most common cancer and the second highest cause of cancer deaths globally. More than 70% of CRC-related deaths are due to metastasis to the liver. The cancer stem cell (CSC) concept hypothesises that CSCs drive tumour growth, chemoresistance, recurrence and metastasis. Markers such as CD133, LGR5 and EpCAM, have been used to identify and isolate CSCs in CRC. However, these markers are often expressed by cells with no stem cell properties and are not expressed by all tumour-initiating cells. An improved range of markers to define CSCs is needed. In 2007, adult mouse and human fibroblasts were reprogrammed into a stem cell state and defined as induced pluripotent stem cells (iPSCs) using transcription factors OCT4, SOX2, NANOG, KLF4 and c-MYC. These genes have well-documented roles in embryonic development and the maintenance of pluripotency, and their expression has been investigated in a range of cancers. <br><br>The renin-angiotensin system (RAS) physiologically maintains blood pressure and volume and is also acknowledged to play a role in cancer. Over-expression of (pro)renin receptor (PRR), angiotensin II type 1 receptor (AT1R) and type 2 receptor (AT2R), and angiotensin-converting enzyme (ACE) have been reported in cancer. Epidemiological studies investigating the effect of RAS inhibitors on cancer outcomes have shown contradictory results.<br><br>This thesis investigates the expression of iPSC markers and RAS components in colon adenocarcinoma (CA) with three specific aims: (1) to compare CA-derived primary cell lines to their original CA tissues; (2) to investigate the expression profiles of iPSC markers in CA; and (3) to investigate expression of RAS components by CA CSCs and to determine whether CSCs can be targeted by RAS modulators. <br><br>DNA sequencing was carried out to compare the mutational profiles of formalin-fixed paraffin-embedded (FFPE) CA tissues and CA-derived cell lines to confirm whether the cell lines were a suitable in vitro model for the parent tumours.<br><br><div>Proteomics was performed to determine proteomic differences between CA tissues and patient-matched normal colon (NC) tissues, CA-derived cell lines and NC-derived cells, and between low grade CA (LGCA) tissues and cell lines and high grade CA (HGCA) tissues and cell lines. Biological processes which may link the RAS and CA were investigated, revealing enrichment of various signalling pathways that may play roles in CA onset and progression directly or via the RAS.</div><div><br></div>Western blotting and immunohistochemical staining showed elevated protein levels of OCT4, SOX2, NANOG, c-MYC, AT2R, PRR and cathepsin D in CA tissues relative to their patient-matched NC tissues, with SOX2, ACE and cathepsin B at similar levels and KLF4 less abundant in CA compared with NC tissues. Co-expression analysis by immunofluorescence staining showed a small number of epithelial cells co-expressed NANOG, SOX2, KLF4, c-MYC and CD133, as well as PRR, ACE2 and AT2R, while a small number of stromal cells co-expressed OCT4 and AT2R. This indicates the presence of at least one CSC subpopulation in CA, which expresses RAS components. HGCA tissue-derived cell lines expressed higher levels of OCT4 and SOX2 than LGCA-derived cell lines. The primary cell lines were sorted based on EpCAM expression. These EpCAM High and EpCAM Low cell subpopulations could undergo directed differentiation down the three embryonic lineages. A small number of CA-derived cells, particularly within the HGCA-derived cells, formed tumourspheres. Treatment of HGCA-derived cell lines with RAS modulators revealed that β-blockers and AT2R antagonists consistently reduced their metabolism, tumoursphere formation and iPSC marker expression. <br><br>The findings of this thesis suggest that CA-derived cell lines expressing iPSC markers have stem cell function and express RAS components. Furthermore, RAS modulators may directly influence CSCs in CA by reducing iPSC marker gene expression. This indicates a potential role for RAS modulators in regulating CSCs, which merits further investigation.

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“…Although CRC is curable, the survival rates are still low. With the current advancements in the world of nanomedicine, it is expected that utilization of NPs will be a vital future approach in CRC theragnostics (Werner and Heinemann, 2016). Correspondingly, this review primarily elaborates on the dysbiosis condition that leads to the development of CRC, and the clinical aspect of NPs and their limitations based on published research.…”

Section: Introductionmentioning

confidence: 99%

Nanoparticles and Gut Microbiota in Colorectal Cancer

Perumal

Ahmad

Mohd-Zahid

et al. 2021

Front. Nanotechnol.

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Recent years have witnessed an unprecedented growth in the research area of nanomedicine. There is an increasing optimism that nanotechnology applied to medicine will bring significant advances in the diagnosis and treatment of various diseases, including colorectal cancer (CRC), a type of neoplasm affecting cells in the colon or the rectum. Recent findings suggest that the role of microbiota is crucial in the development of CRC and its progression. Dysbiosis is a condition that disturbs the normal microbial environment in the gut and is often observed in CRC patients. In order to detect and treat precancerous lesions, new tools such as nanotechnology-based theranostics, provide a promising option for targeted marker detection or therapy for CRC. Because the presence of gut microbiota influences the route of biomarker detection and the route of the interaction of nanoparticle/drug complexes with target cells, the development of nanoparticles with appropriate sizes, morphologies, chemical compositions and concentrations might overcome this fundamental barrier. Metallic particles are good candidates for nanoparticle-induced intestinal dysbiosis, but this aspect has been poorly explored to date. Herein, we focus on reviewing and discussing nanotechnologies with potential applications in CRC through the involvement of gut microbiota and highlight the clinical areas that would benefit from these new medical technologies.

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Standards and Challenges of Care for Colorectal Cancer Today

Cited by 15 publications

References 0 publications

Oxaliplatin resistance in colorectal cancer enhances TRAIL sensitivity via death receptor 4 upregulation and lipid raft localization

Oxaliplatin resistance in colorectal cancer enhances TRAIL sensitivity via death receptor 4 upregulation and lipid raft localization

Characterisation of cancer stem cells and the renin-angiotensin system in colon adenocarcinoma

Nanoparticles and Gut Microbiota in Colorectal Cancer

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