Trop2 and its overexpression in cancers: regulation and clinical/ therapeutic implications

Shvartsur, Anna; Bonavida, Benjamin

doi:10.18632/genesandcancer.40

Cited by 253 publications

(213 citation statements)

References 74 publications

Supporting

Mentioning

205

Contrasting

Unclassified

Order By: Relevance

“…Additional studies are needed to further evaluate the functional importance of the HAI/matriptase/TROP/claudin pathway in skin and to determine if some rare, or perhaps common, skin diseases are a consequence of dysregulation of this pathway. EpCAM, TROP2, claudins, matriptase, and HAI proteins have all been reported roles in cancer [38][39][40][41][42][43][44][45]. Our demonstration of the physiological relationship among these proteins may offer clues for a better understanding of their roles in cancer at molecular level.…”

Section: Discussionmentioning

confidence: 89%

Matriptase Cleaves EpCAM and TROP2 in Keratinocytes, Destabilizing Both Proteins and Associated Claudins

et al. 2020

Cells

View full text Add to dashboard Cite

The homologs EpCAM and TROP2, which both interact with claudin-1 and claudin-7, are frequently coexpressed in epithelia including skin. Intestine uniquely expresses high levels of EpCAM but not TROP2. We previously identified EpCAM as a substrate of the membrane-anchored protease matriptase and linked HAI-2, matriptase, EpCAM and claudin-7 in a pathway that is pivotal for intestinal epithelial cells (IEC) homeostasis. Herein, we reveal that TROP2 is also a matriptase substrate. Matriptase cleaved TROP2 when purified recombinant proteins were mixed in vitro. TROP2, like EpCAM, was also cleaved after co-transfection of matriptase in 293T cells. Neither EpCAM nor TROP2 cleavage was promoted by protease-disabled matriptase or matriptase that harbored the ichthyosis-associated G827R mutation. We confirmed that EpCAM and TROP2 are both expressed in skin and detected cleavage of these proteins in human keratinocytes (HaCaT cells) after the physiologic inhibition of matriptase by HAI proteins was relieved by siRNA knockdown. Knockdown of EpCAM or TROP2 individually had only small effects on claudin-1 and claudin-7 levels, whereas elimination of both markedly diminished claudin levels. HAI-1 knockdown promoted EpCAM and TROP2 cleavage accompanied by reductions in claudins, whereas HAI-2 knockdown had little impact. Double knockdown of HAI-1 and HAI-2 induced nearly complete cleavage of EpCAM and TROP2 and drastic reductions of claudins. These effects were eliminated by concurrent matriptase knockdown. Decreases in claudin levels were also diminished by the lysosomal inhibitor chloroquine and cleaved EpCAM/TROP2 fragments accumulated preferentially. We demonstrate that TROP2 and EpCAM exhibit redundancies with regard to regulation of claudin metabolism and that an HAI, matriptase, EpCAM and claudin pathway analogous to what we described in IECs exists in keratinocytes. This study may offer insights into the mechanistic basis for matriptase dysregulation-induced ichthyosis.

show abstract

Section: Discussionmentioning

confidence: 89%

Matriptase Cleaves EpCAM and TROP2 in Keratinocytes, Destabilizing Both Proteins and Associated Claudins

et al. 2020

Cells

View full text Add to dashboard Cite

show abstract

“…MMP7 and ALDH1A3, that are stem cell markers for squamous cell carcinoma [ 29 , 30 ], were not expressed in neither treated nor untreated tumors. TACSTD as marker for tumor aggressiveness [ 31 ] was not present in relevant abundance either. GLUT1, that may reflect the grade of malignancy [ 32 ], showed upregulation 48 h after mTHPC mediated PDT but not after Lipidot-PDT.…”

Section: Resultsmentioning

confidence: 99%

Lipid nanoemulsions and liposomes improve photodynamic treatment efficacy and tolerance in CAL-33 tumor bearing nude mice

et al. 2016

View full text Add to dashboard Cite

BackgroundPhotodynamic therapy (PDT) as promising alternative to conventional cancer treatments works by irradiation of a photosensitizer (PS) with light, which creates reactive oxygen species and singlet oxygen (1O2), that damage the tumor. However, a routine use is hindered by the PS’s poor water solubility and extended cutaneous photosensitivity of patients after treatment. In our study we sought to overcome these limitations by encapsulation of the PS m-tetrahydroxyphenylchlorin (mTHPC) into a biocompatible nanoemulsion (Lipidots).ResultsIn CAL-33 tumor bearing nude mice we compared the Lipidots to the existing liposomal mTHPC nanoformulation Foslip and the approved mTHPC formulation Foscan. We established biodistribution profiles via fluorescence measurements in vivo and high performance liquid chromatography (HPLC) analysis. All formulations accumulated in the tumors and we could determine the optimum treatment time point for each substance (8 h for mTHPC, 24 h for Foslip and 72 h for the Lipidots). We used two different light doses (10 and 20 J/cm2) and evaluated immediate PDT effects 48 h after treatment and long term effects 14 days later. We also analyzed tumors by histological analysis and performing reverse transcription real-time PCR with RNA extracts. Concerning tumor destruction Foslip was superior to Lipidots and Foscan while with regard to tolerance and side effects Lipidots were giving the best results.ConclusionsWe could demonstrate in our study that nanoformulations are superior to the free PS mTHPC. The development of a potent nanoformulation is of major importance because the free PS is related to several issues such as poor bioavailability, solubility and increased photosensibility of patients. We could show in this study that Foslip is very potent in destroying the tumors itself. However, because the Lipidots' biocompatibility is outstanding and superior to the liposomes we plan to carry out further investigations and protocol optimization. Both nanoformulations show great potential to revolutionize PDT in the future.Electronic supplementary materialThe online version of this article (doi:10.1186/s12951-016-0223-8) contains supplementary material, which is available to authorized users.

show abstract

“…This has been attributed to the down regulation of the Ras-Raf and PI3K-Akt pathways [68]. Other targets in HCC include: glypican-3 (GC33), c-Met (onartuzumab), epidermal growth factor receptor (cetuximab), insulin-like growth factor-1 receptor (cixutumumab), insulin-like growth factor I and II (MEDI-573), platelet-derived growth factor receptor A (MEDI-575), activin receptor-like kinase 1 (PF-03446962), endoglin (TRC105), and TROP-2 (sacituzumab) [69,70,71,72,73,74,75]. Additional targets like EpCAM and CD133 are being evaluated in preclinical studies as potential markers for HCC [45,76,77,78].…”

Section: Anti-gpc3 Recombinant Immunotoxinsmentioning

confidence: 99%

Glypican-3 Targeting Immunotoxins for the Treatment of Liver Cancer

Fleming

2016

Toxins

View full text Add to dashboard Cite

Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer, yet no effective therapeutics exist. This review provides an overview of the recent development of recombinant immunotoxins for the treatment of glypican-3 (GPC3) expressing HCC. GPC3 is a cell surface heparan sulfate proteoglycan that is overexpressed in HCC, but is absent from normal adult human tissues. Treatment of HCC with anti-GPC3 immunotoxins represents a new therapeutic option. Using phage display and hybridoma technologies, three high affinity antibodies (HN3, HS20 and YP7) have been generated against GPC3. Two of these antibodies (HN3 and HS20) have demonstrated the ability to inhibit Wnt/Yap signaling, leading to a reduction in liver cancer cell proliferation. By combining the HN3 antibody capable of inhibiting Wnt/Yap signaling with the protein synthesis inhibitory domain of the Pseudomonas exotoxin, a recombinant immunotoxin that exhibits a dual inhibitory mechanism was generated. This immunotoxin was found to be highly effective in the treatment of human HCCs in mouse xenograft models. Engineering of the toxin fragment to reduce the level of immunogenicity is currently being explored. The development of immunotoxins provides opportunities for novel liver cancer therapies.

show abstract

Trop2 and its overexpression in cancers: regulation and clinical/ therapeutic implications

Cited by 253 publications

References 74 publications

Matriptase Cleaves EpCAM and TROP2 in Keratinocytes, Destabilizing Both Proteins and Associated Claudins

Matriptase Cleaves EpCAM and TROP2 in Keratinocytes, Destabilizing Both Proteins and Associated Claudins

Lipid nanoemulsions and liposomes improve photodynamic treatment efficacy and tolerance in CAL-33 tumor bearing nude mice

Glypican-3 Targeting Immunotoxins for the Treatment of Liver Cancer

Contact Info

Product

Resources

About