Expression and Localization of Cathepsins B, D and G in Cancer Stem Cells in Liver Metastasis From Colon Adenocarcinoma

Mehrotra, Shreeja; Wickremesekera, Susrutha K.; Brasch, Helen D.; Schaijik, Bede van; Marsh, Reginald; Tan, Swee T.; Itinteang, Tinte

doi:10.3389/fsurg.2018.00040

Cited by 27 publications

(26 citation statements)

References 39 publications

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“…Cathepsins B, D and G are proteases that constitute bypass loops for the RAS [22] and have been implicated in tumorigenesis and metastasis in CRC due to their ability to degrade extra-cellular matrix. We have shown the expression of cathepsin B and cathepsin D by the CSC subpopulations within oral tongue squamous cell carcinoma [27] , GB [39] and more recently LMCA [34] , implying the presence of bypass loops for the RAS.…”

Section: Discussionmentioning

confidence: 81%

“…Recent literature suggests a critical role for the RAS in cancer growth and metastasis [24] . There is increasing appreciation of the complex interplay between the RAS and other pathways including IGF, VEGF, and potential bypass loops consisting of cathepsins B, D and G [22,34] . These related pathways are implicated in a number of biological processes such as angiogenesis, cell migration, tumorigenesis and hematopoiesis which may create a conducive environment for carcinogenesis by promoting the proliferation of CSCs [22] .…”

Section: Discussionmentioning

confidence: 99%

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Cancer stem cells in liver metastasis from colon adenocarcinoma express components of the renin-angiotensin system

Narayanan¹,

Wickremesekera²,

Schaijik³

et al. 2019

JCMT

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Aim: We have recently identified a cancer stem cell (CSC) subpopulations within the tumor nests (TNs) and another within the peritumoral stroma (PTS) in liver metastasis from colon adenocarcinoma (LMCA). This study investigated the expression of components of the renin-angiotensin (RAS): pro-renin receptor (PRR), angiotensin converting enzyme (ACE), and angiotensin II receptor 1 (ATIIR1) and angiotensin II receptor 2 (ATIIR2) in LMCA. Methods: 3,3-Diaminobenzidine (DAB) immunohistochemical (IHC) staining was performed on 16 LMCA samples for PRR, ACE, ATIIR1 and ATIIR2. Immunofluorescence (IF) IHC staining was performed to investigate co-expression of these components of the RAS with SOX2 or OCT4. NanoString analysis (n = 6) and Western blotting (WB, n = 3) were performed on snap-frozen LMCA samples to confirm mRNA and protein expression, respectively. Results: DAB IHC staining showed the expression of PRR, ACE, ATIIR1 and ATIIR2 within all LMCA samples. NanoString analysis and WB confirmed gene and protein expression of these components of the RAS. IF IHC staining demonstrated expression of PRR, ATIIR1 and ATIIR2 by the SOX2 + CSCs within the TNs and the OCT4 + CSCs within the PTS. ACE was expressed on the endothelium of the microvessels within the PTS. Conclusion: These finding suggests the CSCs within LMCA maybe a novel therapeutic target by manipulation of the RAS.

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Section: Discussionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Cancer stem cells in liver metastasis from colon adenocarcinoma express components of the renin-angiotensin system

Narayanan¹,

Wickremesekera²,

Schaijik³

et al. 2019

JCMT

Self Cite

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“…As a metastasin, S100A4 is associated with numerous cytoskeletal proteins, such as actin, myosin, and tropomyosin, increasing the tumor progression and metastasis (19,(25)(26)(27). Cathepsin B belongs to a family of lysosomal cysteine proteases comprising disulfide-linked heavy and light chains, which can directly or indirectly degrade the extracellular matrix in tumor tissues (28). Inhibition of cathepsin B could reduce liver metastases of CRC (29).…”

Section: Discussionmentioning

confidence: 99%

Molecular Mechanisms by Which S100A4 Regulates the Migration and Invasion of PGCCs With Their Daughter Cells in Human Colorectal Cancer

Fei

et al. 2020

Front. Oncol.

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Recently, an increasing number of evidences have shown that polyploid giant cancer cells (PGCCs) could generate daughter cells with a strong migration and invasion ability, which have been implicated in cancer recurrence and metastasis. However, the underlying molecular mechanisms of PGCCs with their daughter cells remain largely unclear. In vitro and in vivo experiments combined with 222 cases of human colorectal cancer (CRC) samples were used to identify the molecular mechanisms of S100A4-related proteins regulating the invasion and metastasis of PGCCs with their daughter cells. PGCCs with their daughter cells had high migration, invasion, and proliferation abilities compared to control cells; these were significantly inhibited after S100A4 knockdown. The high expression of cathepsin B, cyclin B1, TRIM21, and Annexin A2 were significantly downregulated after S100A4 knockdown, while the overexpression of S100A4, cathepsin B, cyclin B1, and S100A10 were significantly downregulated after TRIM21 knockdown in PGCCs with their daughter cells. The tumorigenic and metastatic ability of PGCCs with their daughter cells in vivo was significantly stronger compared to the untreated cells, which was significantly decreased after S100A4 knockdown. Moreover, the expression of S100A4-related proteins was positively correlated with the malignancy degree of human CRC, and maintained a high level in lymph node metastasis. S100A4 and TRIM21 may regulate each other to affect the expression and subcellular localization of cyclin B1, and participate in regulating the structure and function of Annexin A2/S100A10 complex, affecting downstream cathepsin B, resulting in the invasion and metastasis of PGCCs with their daughter cells. Besides, 14-3-3 ζ/δ and Ezrin may be involved in the motility and invasion of PGCCs with their daughter cells via cytoskeletal constructions with S100A4.

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“…Hence, the intimate relationships between Cathepsins and cancer stimulated the conception of (macro)molecules sensitive to the presence of Cathepsins for enhanced therapeutic effect. [71][72][73][74][75][76][77] In the following, we have covered Cathepsin-sensitive drug delivery systems for anticancer therapy, by distinguishing five different types of systems: (i) polymeric; (ii) inorganic; (iii) dendritic/comb-like; (iv) lipidic and (v) protein-based/peptidic.…”

Section: Cathepsin-sensitive Drug Delivery Systems 21 Anticancer Drumentioning

confidence: 99%

Cathepsin-sensitive nanoscale drug delivery systems for cancer therapy and other diseases

Dheer

Nicolas

Shankar

2019

Advanced Drug Delivery Reviews

101

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Cathepsins are an important category of enzymes that have attracted great attention for the delivery of drugs to improve the therapeutic outcome of a broad range of nanoscale drug delivery systems. These proteases can be utilized for instance through actuation of polymer-drug conjugates (e.g., triggering the drug release) to bypass limitations of many drug candidates. A substantial amount of work has been witnessed in the design and the evaluation of Cathepsinsensitive drug delivery systems, especially based on the tetra-peptide sequence (Gly-Phe-Leu-Gly, GFLG) which has been extensively used as a spacer that can be cleaved in the presence of Cathepsin B. This Review Article will give an in-depth overview of the design and the biological evaluation of Cathepsin-sensitive drug delivery systems and their application in different pathologies including cancer before discussing Cathepsin B-cleavable prodrugs under clinical trials.

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Expression and Localization of Cathepsins B, D and G in Cancer Stem Cells in Liver Metastasis From Colon Adenocarcinoma

Cited by 27 publications

References 39 publications

Cancer stem cells in liver metastasis from colon adenocarcinoma express components of the renin-angiotensin system

Cancer stem cells in liver metastasis from colon adenocarcinoma express components of the renin-angiotensin system

Molecular Mechanisms by Which S100A4 Regulates the Migration and Invasion of PGCCs With Their Daughter Cells in Human Colorectal Cancer

Cathepsin-sensitive nanoscale drug delivery systems for cancer therapy and other diseases

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