Cathepsin L secretion by host and neoplastic cells potentiates invasion

Dykes, Samantha S.; Fasanya, Henrietta O.; Siemann, Dietmar W.

doi:10.18632/oncotarget.27182

Cited by 20 publications

(18 citation statements)

References 41 publications

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“…Soluble/secreted EpCAM (EpEX) is a 242 amino acid (aa) fragment lacking the signal peptide (23 aa), transmembrane domain (23 aa), and cytoplasmic tail (26 aa) [ 13 ]. CTSL, while typically expressed in the endosome, has also been shown to be secreted by tumor cells and potentiates invasion in multiple cancer types [ 37 , 38 ]. A study of congenital tufting enteropathy patients demonstrated that some EpCAM germline mutations can alter cellular trafficking and localization of EpCAM protein to the cell surface [ 30 ].…”

Section: Resultsmentioning

confidence: 99%

Cancer-associated mutations reveal a novel role for EpCAM as an inhibitor of cathepsin-L and tumor cell invasion

et al. 2021

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Background EpCAM (Epithelial cell adhesion molecule) is often dysregulated in epithelial cancers. Prior studies implicate EpCAM in the regulation of oncogenic signaling pathways and epithelial-to-mesenchymal transition. It was recently demonstrated that EpCAM contains a thyroglobulin type-1 (TY-1) domain. Multiple proteins with TY-1 domains are known to inhibit cathepsin-L (CTSL), a cysteine protease that promotes tumor cell invasion and metastasis. Analysis of human cancer sequencing studies reveals that somatic EpCAM mutations are present in up to 5.1% of tested tumors. Methods The Catalogue of Somatic Mutations in Cancer (COSMIC) database was queried to tabulate the position and amino acid changes of cancer associated EpCAM mutations. To determine how EpCAM mutations affect cancer biology we studied C66Y, a damaging TY-1 domain mutation identified in liver cancer, as well as 13 other cancer-associated EpCAM mutations. In vitro and in vivo models were used to determine the effect of wild type (WT) and mutant EpCAM on CTSL activity and invasion. Immunoprecipitation and localization studies tested EpCAM and CTSL protein binding and determined compartmental expression patterns of EpCAM mutants. Results We demonstrate that WT EpCAM, but not C66Y EpCAM, inhibits CTSL activity in vitro, and the TY-1 domain of EpCAM is responsible for this inhibition. WT EpCAM, but not C66Y EpCAM, inhibits tumor cell invasion in vitro and lung metastases in vivo. In an extended panel of human cancer cell lines, EpCAM expression is inversely correlated with CTSL activity. Previous studies have demonstrated that EpCAM germline mutations can prevent EpCAM from being expressed at the cell surface. We demonstrate that C66Y and multiple other EpCAM cancer-associated mutations prevent surface expression of EpCAM. Cancer-associated mutations that prevent EpCAM cell surface expression abrogate the ability of EpCAM to inhibit CTSL activity and tumor cell invasion. Conclusions These studies reveal a novel role for EpCAM as a CTSL inhibitor, confirm the functional relevance of multiple cancer-associated EpCAM mutations, and suggest a therapeutic vulnerability in cancers harboring EpCAM mutations.

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Section: Resultsmentioning

confidence: 99%

Cancer-associated mutations reveal a novel role for EpCAM as an inhibitor of cathepsin-L and tumor cell invasion

et al. 2021

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“…Including cathepsins, other proteases such as urokinase-type plasminogen activator (uPA), tissue plasminogen activator (tPA), elastases, and matrix metalloproteinases (MMPs) form a cascade of proteolytic activation to facilitate degradation of extracellular matrix [282]. In models of breast cancer, TAM-derived cathepsin B [283], X [283], and L [284] were requisite for tumor cell invasion and metastasis. Likewise, cathepsin B [280], S [280], and X [191] from TAMs contributed to tumor cell invasion in pancreatic cancer.…”

Section: Role Of Cathepsins In Function Of Tamsmentioning

confidence: 99%

“…Likewise, cathepsin B [280], S [280], and X [191] from TAMs contributed to tumor cell invasion in pancreatic cancer. IL-4 has been repeatedly accused of stimulating cathepsin secretion in TAMs [254,280,284]. Besides secreted cathepsins, cathepsins in lysosomes of TAMs could be responsible for the digestion of internalized collagen fragment from tumor microenvironment [285].…”

Section: Role Of Cathepsins In Function Of Tamsmentioning

confidence: 99%

Role of lysosomes in physiological activities, diseases, and therapy

Zhang¹,

Yue

et al. 2021

J Hematol Oncol

177

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Long known as digestive organelles, lysosomes have now emerged as multifaceted centers responsible for degradation, nutrient sensing, and immunity. Growing evidence also implicates role of lysosome-related mechanisms in pathologic process. In this review, we discuss physiological function of lysosomes and, more importantly, how the homeostasis of lysosomes is disrupted in several diseases, including atherosclerosis, neurodegenerative diseases, autoimmune disorders, pancreatitis, lysosomal storage disorders, and malignant tumors. In atherosclerosis and Gaucher disease, dysfunction of lysosomes changes cytokine secretion from macrophages, partially through inflammasome activation. In neurodegenerative diseases, defect autophagy facilitates accumulation of toxic protein and dysfunctional organelles leading to neuron death. Lysosomal dysfunction has been demonstrated in pathology of pancreatitis. Abnormal autophagy activation or inhibition has been revealed in autoimmune disorders. In tumor microenvironment, malignant phenotypes, including tumorigenesis, growth regulation, invasion, drug resistance, and radiotherapy resistance, of tumor cells and behaviors of tumor-associated macrophages, fibroblasts, dendritic cells, and T cells are also mediated by lysosomes. Based on these findings, a series of therapeutic methods targeting lysosomal proteins and processes have been developed from bench to bedside. In a word, present researches corroborate lysosomes to be pivotal organelles for understanding pathology of atherosclerosis, neurodegenerative diseases, autoimmune disorders, pancreatitis, and lysosomal storage disorders, and malignant tumors and developing novel therapeutic strategies.

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“…Further studies revealed that STAT3 and STAT6 promote cathepsin secretion by macrophages [56]. Recently, a study showed that inhibition of cathepsin L secretion by TAMs and breast cancer cells impairs invasion and M2-like TAM infiltration in the tumor microenvironment [57]. The macrophage inflammatory proteins 1α (MIP-1α or CCL3) and -β (MIP-1β or CCL4) are chemokines of the CC superfamily derived from immune cells, including macrophages.…”

Section: Tams In Cancer Cell Invasionmentioning

confidence: 99%

Contribution of Macrophages and T Cells in Skeletal Metastasis

Mendoza-Reinoso

McCauley

Fournier

2020

Cancers

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Bone is a common site for metastases with a local microenvironment that is highly conducive for tumor establishment and growth. The bone marrow is replete with myeloid and lymphoid linage cells that provide a fertile niche for metastatic cancer cells promoting their survival and growth. Here, we discuss the role of macrophages and T cells in pro- and anti-tumoral mechanisms, their interaction to support cancer cell growth, and their contribution to the development of skeletal metastases. Importantly, immunotherapeutic strategies targeting macrophages and T cells in cancer are also discussed in this review as they represent a great promise for patients suffering from incurable bone metastases.

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Cathepsin L secretion by host and neoplastic cells potentiates invasion

Cited by 20 publications

References 41 publications

Cancer-associated mutations reveal a novel role for EpCAM as an inhibitor of cathepsin-L and tumor cell invasion

Cancer-associated mutations reveal a novel role for EpCAM as an inhibitor of cathepsin-L and tumor cell invasion

Role of lysosomes in physiological activities, diseases, and therapy

Contribution of Macrophages and T Cells in Skeletal Metastasis

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