Immunostained cathepsins B and L correlate with depth of invasion and different metastatic pathways in early stage gastric carcinoma

Dohchin, Akiharu; Suzuki, Jun–ichi; Masutani, Manabu; Shiroto, Hiroshi; Kawakami, Yoshikazu

doi:10.1002/1097-0142(20000801)89:3<482::aid-cncr2>3.3.co;2-x

Cited by 12 publications

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“…Procathepsin‐L secreted by the INSL3 transfectants may itself have an important role in the formation, vascularization, and growth of these xenograft tumors. Cathepsin‐L promotes the migration and basement membrane degradation by tumor cells55, 56 and facilitates neovascularization in vivo by enhancing the proteolytic, promigratory capacity of endothelial progenitor cells 57. Thus, both INSL3 target molecules, S100A4, and procathepsin‐L, may support a microenvironment within the grafts which is conducive to rapid tumor growth.…”

Section: Discussionmentioning

confidence: 99%

INSL3 has tumor‐promoting activity in thyroid cancer

Hombach‐Klonisch

Białek

Radestock

et al. 2010

Intl Journal of Cancer

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The functional role of INSL3 and its receptor RXFP2 in carcinogenesis is largely unknown. We have previously demonstrated (pro-)cathepsin-L as a target of INSL3 in human thyroid cancer cells facilitating penetration of tumor cells through elastin matrices. We demonstrate the expression of RXFP2 in human thyroid tissues and in mouse follicular thyroid epithelial cells using Cre-recombinase transgene driven by Rxfp2 promoter. Recombinant and secreted INSL3 increased the motility of thyroid carcinoma (TC) cells in an autocrine/paracrine manner. This effect required the presence of RXFP2. We identified S100A4 as a novel INSL3 target molecule and showed that S100A4 facilitated INSL3-induced enhanced motility. Stable transfectants of the human follicular TC cell line FTC-133 expressing and secreting bioactive human INSL3 displayed enhanced anchorageindependent growth in soft agar assays. Xenotransplant experiments in nude mice showed that INSL3, but not EGFP-mock transfectants, developed fast-growing and highly vascularized xenografts. We used human umbilical vein endothelial cells in capillary tube formation assays to demonstrate increased 2-dimensional tube formations induced by recombinant human INSL3 and human S100A4 comparable to the effect of vascular endothelial growth factor used as positive control. We conclude that INSL3 is a powerful and multifunctional promoter of tumor growth and angiogenesis in human thyroid cancer cell xenografts. INSL3 actions involve RXFP2 activation and the secretion of S100A4 and (pro-)cathepsin-L.Comprising 1% of all malignancies, thyroid cancer is the most common carcinoma of endocrine glands and displays the highest increase in incidence of all malignancies in the United States over the time interval 1975-2000 (http://seer. cancer.gov/csr/1975_2004/; www.cancer.ca). 1 There are 4 types of thyroid carcinoma (TC) that comprise >98% of all thyroid malignancies: papillary (PTC), follicular (FTC), anaplastic, undifferentiated (UTC) and medullary TC (MTC). We showed previously that the insulin-like peptide hormone, insulin-like peptide 3 (INSL3) and a novel INSL3 splice form are present in human hyperplastic thyroid adenoma and thyroid cancer. 2 INSL3 is a member of the relaxin family and signals through the type C leucine-rich repeat G proteincoupled receptor RXFP2, also named GREAT and LGR8. [3][4][5][6][7] Activation of RXFP2 causes an increase in cAMP levels and, via the actions of the small G-proteins Ga s and Ga oB , activates and negatively modulates adenylate cyclase activity, respectively, which affects cAMP-response element transcriptional activity. [8][9][10] Deletion of the gene for INSL3 or the INSL3 receptor causes impaired transabdominal testis descent and cryptorchidism in rodents and boys. [11][12][13][14] Both INSL3 and the homologous peptide relaxin are found in tumor tissues but little information is currently available on the functional role of both the INSL3-RXFP2 and the relaxin-RXFP1 system in cancer cells. 15 In prostate cancer, increasing evidence from cell an...

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Section: Discussionmentioning

confidence: 99%

INSL3 has tumor‐promoting activity in thyroid cancer

Hombach‐Klonisch

Białek

Radestock

et al. 2010

Intl Journal of Cancer

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“…Previous Cathepsin L immunohistochemistry studies have identified granular cytoplasmic staining patterns in sarcomas, oral squamous cell carcinomas, gastric cancers and gliomas 17–20. Quantitative RNA slot blot analysis has shown that kidney and testicular tumors express the highest levels of Cathepsin L compared to nonsmall cell carcinomas of the lung and many cancers including breast, ovary, colon, adrenal, bladder, prostate and thyroid cancers 21…”

Section: Discussionmentioning

confidence: 99%

Localization of nuclear cathepsin L and its association with disease progression and poor outcome in colorectal cancer

Sullivan

Tosetto

Kevans

et al. 2009

Intl Journal of Cancer

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Previous in vitro studies have identified a nuclear isoform of Cathepsin L. The aim of this study was to examine if nuclear Cathepsin L exists in vivo and examine its association with clinical, pathological and patient outcome data. Cellular localization (nuclear and cytoplasmic) and expression levels v of Cathespin L in 186 colorectal cancer cases using immunohistochemistry. The molecular weight and activity of nuclear and cytoplasmic Cathepsin L in vivo and in vitro were assessed by Western blotting and ELISA, respectively. Epithelial nuclear staining percentage (p 5 0.04) and intensity (p 5 0.006) increased with advancing tumor stage, whereas stromal cytoplasmic staining decreased (p 5 0.02). Using multivariate statistical analysis, survival was inversely associated with staining intensity in the epithelial cytoplasm (p 5 0.01) and stromal nuclei (p 5 0.007). In different colorectal cell lines and in vivo tumors, pro-and active Cathepsin L isoforms were present in both the cytoplasm and nuclear samples, with pro-Cathepsin L at 50 kDa and active Cathepsin L at 25 kDa. Purified nuclear and cytoplasmic fractions from cell lines and tumors showed active Cathepsin L activity. The identification of nuclear Cathepsin L may play an important prognostic role in colorectal disease progression and patient outcome. Moreover, these findings suggest that altering active nuclear Cathepsin L may significantly influence disease progression. ' UICCKey words: colorectal cancer; cathepsin L; disease progression; survival Colorectal cancer is one of the most common cancers in the Western World. Tumor invasion and metastasis are major causes of treatment failure 1 and this multi-step process involves penetration of host extracellular matrix (ECM) by cancer cells, which invade the host stroma and enter the circulation. The outcome of metastasis is dependent on the interaction between the intrinsic properties of the tumor cells and various host factors, and this balance may vary from patient to patient. 2,3 The ability of tumor cells to invade tissues and metastasize is thought to involve an increased expression and activity of proteases including cathepsins. 4,5 Tumor spread is also correlated with increased levels of these activated enzymes. 6 The cysteine protease, Cathepsin L, is thought to participate in tumor cell invasion, although its exact role remains unknown. 7 The Cathepsin L gene is activated by a variety of growth factors and oncogenes. 8 It is initially synthesized as a 334-amino acid precursor containing a 17-amino acid N-terminal signal peptide followed by a 96-amino acid propeptide. 9-11 Pro-Cathepsin L is an inactive precursor and is processed to a single chain form of mature Cathepsin L, which can be further cleaved to the two-chain forms, linked to a light-chain by disulfide bonds. 12,13 Pro-and active forms of Cathepsin L differ in size depending on the species, tissue and cell line investigated. Colorectal cancers have been profiled based on the levels of different cysteine proteases including Cathepsin L. 1...

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“…CTSL localizes primarily to the lysosomes and is also a constituent of the nuclear protein fraction. Although previous studies have shown that CTSL is upregulated in GC and could be identified as a marker of enhanced invasiveness of GC [10,15,30], the function of nuclear CTSL in GC angiogenesis has not been determined. In this study, we found that nuclear CTSL is significantly upregulated in GC cancer and predicts poor prognosis of GC patients.…”

Section: Ctsl Expression Is Positively Correlated With Vegf-d In Gc Tmentioning

confidence: 99%

Cathepsin L promotes angiogenesis by regulating the CDP/Cux/VEGF-D pathway in human gastric cancer

et al. 2020

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Background Increasing evidence indicates that angiogenesis plays an important role in tumor progression. The function of cathepsin L (CTSL), an endosomal proteolytic enzyme, in promoting tumor metastasis is well recognized. The mechanisms by which CTSL has promoted the angiogenesis of gastric cancer (GC), however, remains unclear. Methods The nuclear expression levels of CTSL were assessed in GC samples. The effects of CTSL on GC angiogenesis were determined by endothelial tube formation analysis, HUVEC migration assay, and chick embryo chorioallantoic membrane (CAM) assay. The involvement of the CDP/Cux/VEGF-D pathway was analyzed by angiogenesis antibody array, Western blot, co-immunoprecipitation (Co-IP) and dual-luciferase reporter assay. Results In this study, we found that the nuclear CTSL expression level in GC was significantly higher than that in adjacent nontumor gastric tissues and was a potential important clinical prognostic factor. Loss- and gain-of-function assays indicated that CTSL promotes the tubular formation and migration of HUVEC cells in vitro. The CAM assay also showed that CTSL promotes angiogenesis of GC in vivo. Mechanistic analysis demonstrated that CTSL can proteolytically process CDP/Cux and produce the physiologically relevant p110 isoform, which stably binds to VEGF-D and promotes the transcription of VEGF-D, thus contributing to the angiogenesis of GC. Conclusion The findings of the present study suggested that CTSL plays a constructive role in the regulation of angiogenesis in human GC and could be a potential therapeutic target for GC.

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Immunostained cathepsins B and L correlate with depth of invasion and different metastatic pathways in early stage gastric carcinoma

Cited by 12 publications

References 0 publications

INSL3 has tumor‐promoting activity in thyroid cancer

INSL3 has tumor‐promoting activity in thyroid cancer

Localization of nuclear cathepsin L and its association with disease progression and poor outcome in colorectal cancer

Cathepsin L promotes angiogenesis by regulating the CDP/Cux/VEGF-D pathway in human gastric cancer

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