Cathepsin K associates with lymph node metastasis and poor prognosis in oral squamous cell carcinoma

Leusink, Frank K.J.; Koudounarakis, Eleftherios; Frank, Michael; Koole, R.; Diest, Paul J. van; Willems, Stefan M.

doi:10.1186/s12885-018-4315-8

Cited by 31 publications

(15 citation statements)

References 33 publications

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“…Besides, the upregulation of CatK in the psoriatic lesions of patients with psoriasis was documented by Hirai et al (2013). Coincidently, the upregulated CatK was found to be associated with oral squamous cell carcinoma (OSCC), in which CatK may be served as a predictive biomarker according to the study by Leusink et al (2018).…”

Section: Other Organs and Systemsmentioning

confidence: 93%

Cathepsin K: The Action in and Beyond Bone

Dai

Chu

et al. 2020

Front. Cell Dev. Biol.

127

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Cathepsin K (CatK) is one of the most potent proteases in lysosomal cysteine proteases family, of which main function is to mediate bone resorption. Currently, CatK is among the most attractive targets for anti-osteoporosis drug development. Although many pharmaceutical companies are working on the development of selective inhibitors for CatK, there is no FDA approved drug till now. Odanacatib (ODN) developed by Merck & Co. is the only CatK inhibitor candidate which demonstrated high therapeutic efficacy in patients with postmenopausal osteoporosis in Phase III clinical trials. Unfortunately, the development of ODN was finally terminated due to the cardio-cerebrovascular adverse effects. Therefore, it arouses concerns on the undesirable CatK inhibition in non-bone sites. It is known that CatK has far-reaching actions throughout various organs besides bone. Many studies have also demonstrated the involvement of CatK in various diseases beyond the musculoskeletal system. This review not only summarized the functional roles of CatK in bone and beyond bone, but also discussed the potential relevance of the CatK action beyond bone to the adverse effects of inhibiting CatK in non-bone sites.

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Section: Other Organs and Systemsmentioning

confidence: 93%

Cathepsin K: The Action in and Beyond Bone

Dai

Chu

et al. 2020

Front. Cell Dev. Biol.

127

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“…Human CTSK participates in a considerable number of physiological processes, including MHC-II-mediated antigen presentation, bone remodeling, keratinocyte differentiation, and prohormone activation [9]. CTSK could also be detected in several cancer types including oral squamous cell carcinoma [10], breast cancer [11], ovarian cancer [12], and glioblastoma [13]. Despite its well-known function in cleaving and activating MM9 to degrade and remodel the tumor extracellular matrix [14], tumor-secreted CTSK might also interact with stromal cells in a paracrine manner.…”

Section: Introductionmentioning

confidence: 99%

Gut microbiota-stimulated cathepsin K secretion mediates TLR4-dependent M2 macrophage polarization and promotes tumor metastasis in colorectal cancer

et al. 2019

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Metastasis is a complex process that requires the interaction between tumor cells and their microenvironment. As an important regulator of intestinal microenvironment, gut microbiota plays a significant role in the initiation and progression of colorectal cancer (CRC), but the underlying mechanisms remain elusive. In this study, a metastasis-related secretory protein cathepsin K (CTSK) was identified as a vital mediator between the imbalance of intestinal microbiota and CRC metastasis. We implanted MC38 cells into the cecal mesentry of antibiotic-treated mice with intragastrically administration of E. coli to mimic gut microbiota imbalance. The bigger primary tumors and more liver metastatic foci were detected in the E. coli group accompanied with high LPS secretion and CTSK overexpression compared with that in the control group. CTSK contributes to the aggressive phenotype of CRC cells both in vitro and in vivo. Silencing CTSK or administration of Odanacatib, a CTSK-specific inhibitor, totally abolished the CTSK-enhanced migration and motility of CRC cells. Interestingly, the tumorsecreted CTSK could bind to toll-like receptor 4 (TLR4) to stimulate the M2 polarization of tumor-associated macrophages (TAMs) via an mTOR-dependent pathway. Recombinant CTSK could neither stimulate CRC growth and metastasis, nor induce M2 macrophage polarization in TRL4 −/− mice. Meanwhile, CTSK could stimulate the secretion of cytokines by M2 TAMs including IL10 and IL17, which, in turn, promote the invasion and metastasis of CRC cells through NFκB pathway. Clinically, overexpression of CTSK in human CRC tissues is always accompanied with high M2 TAMs in the stroma, and correlated with CRC metastasis and poor prognosis. Our current research identified CTSK as a mediator between the imbalance of gut microbiota and CRC metastasis. More importantly, we illustrated a CTSK-mediated-positive feedback loop between CRC cells and TAMs during metastasis, prompting CTSK as a novel predictive biomarker and feasible therapeutic target for CRC.

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“…This study concludes and strongly emphasizes on the fact that up regulation of cathepsin K gene expression is a key reason with very high incidence for the occurrence of lymphatic node metastasis and poor survival in oral squamous cell carcinoma and also highlights that the CtsK gene could be used as a predictive biomarker for oral squamous cell carcinoma detection and analysis of the degree of the carcinoma (Leusink et al, 2018). This recent study is therefore a suggestive indication for uplifting recruitment strategies of molecular disease diagnostics; molecular biological techniques especially in oncological medicine for disease detection and validation.…”

Section: Resultsmentioning

confidence: 56%

Potential Role of Cathepsin K in Regulation of Micro Tumor Environment, Onset and Progression of Cancers in Human- A Review

Cooray¹,

Madubashetha²,

Wickramasinghe³

et al. 2020

Preprint

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The effect of proteolytic enzymes including Cathepsin K, a cysteine cathepsin, in onset and progression of cancers in human has been research intensive. Cathepsin K involves in many aspects and stages of cancers including apoptosis, cell proliferation, cancer immunology, inflammatory cell recruitment to tumors and aiding in the process of mobilization of normal healthy cells from their tissue compartments assisting in metastasis and angiogenesis. The objective of this review is to collect together and summarize and analyze the biochemical and physiological pathways of how cathepsin K is involved in onset and progression of cancers with more emphasis on breast and prostate cancers and cathepsin K regulated mechanisms underlying metastasis of such cancers to bones. Information for the review was gathered through published literature from global databases such as Google Scholar, PUBMED and NCBI on different studies on physiological interactions between enzymatic activity of cathepsin K with cancers and metastasis to bones. Analysis of published studies reveal that immunohistochemical studies of breast cancer cells indicate that they overexpress cathepsin K resulting in induction of aberrant mechanisms of cell signaling in breast cancers, creating a higher tendency for their metastasis to bones. Immunohistochemical, immunoprecipitation and fluorgenic assays of several studies done on the association of the same enzymatic activity on prostate cancers shows elevated levels of cathepsin K. Lesions derived from prostate cancer cell masses were observed to undergo increased bone formation and resorption levels. Such resorption levels cause secretion of biological factors promoting tumor expansion. In addition, studies indicate that Cathepsin K was observed to be a key component promoting higher bone resorption levels in patients suffering from cancer. Authors suggest that, to completely understand the association of cathepsin K on cancerous cells and their mechanism in metastasis, distributary patterns of cathepsin K in healthy human tissues needs to be extensively studied initially. It is also suggested that metastasis of breast and prostate cancers to bone could be terminated and overcome by successful production of efficient and precise inhibitory therapeutics targeting the enzymatic activity of Cathepsin K with minimum unintended adverse health effects.

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Cathepsin K associates with lymph node metastasis and poor prognosis in oral squamous cell carcinoma

Cited by 31 publications

References 33 publications

Cathepsin K: The Action in and Beyond Bone

Cathepsin K: The Action in and Beyond Bone

Gut microbiota-stimulated cathepsin K secretion mediates TLR4-dependent M2 macrophage polarization and promotes tumor metastasis in colorectal cancer

Potential Role of Cathepsin K in Regulation of Micro Tumor Environment, Onset and Progression of Cancers in Human- A Review

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