Thymidine phosphorylase promotes angiogenesis and tumour growth in intrahepatic cholangiocarcinoma

Li, Shuangling; Yang, Hongli; Li, Kun; Fan, Guijuan; Deng, Li; Xu, Changqing

doi:10.1002/cbf.3541

Cited by 5 publications

(4 citation statements)

References 40 publications

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“…3B ). In addition, high levels of TYMP in tumor endothelium are linked to increased angiogenesis and a poor prognosis [ 27 – 30 ]. The TYMP inhibitor Tipiracil (TPI), is commonly used in anti-cancer treatments to prevent the degradation of 5-FU and has been shown to prevent thrombosis [ 31 ].…”

Section: Resultsmentioning

confidence: 99%

Thymidine phosphorylase facilitates retinoic acid inducible gene-I induced endothelial dysfunction

et al. 2023

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Activation of nucleic acid sensors in endothelial cells (ECs) has been shown to drive inflammation across pathologies including cancer, atherosclerosis and obesity. We previously showed that enhancing cytosolic DNA sensing by inhibiting three prime exonuclease 1 (TREX1) in ECs led to EC dysfunction and impaired angiogenesis. Here we show that activation of a cytosolic RNA sensor, Retinoic acid Induced Gene 1 (RIG-I) diminishes EC survival, angiogenesis and triggers tissue specific gene expression programs. We discovered a RIG-I dependent 7 gene signature that affects angiogenesis, inflammation and coagulation. Among these, we identified the thymidine phosphorylase TYMP as a key mediator of RIG-I induced EC dysfunction via its regulation of a subset of interferon stimulated genes. Our RIG-I induced gene signature was also conserved in the context of human diseases – in lung cancer vasculature and herpesvirus infection of lung endothelial cells. Pharmacological or genetic inhibition of TYMP rescues RIG-I induced EC death, migration arrest and restores sprouting angiogenesis. Interestingly, using RNAseq we identified a gene expression program that was RIG-I induced but TYMP dependent. Analysis of this dataset indicated that IRF1 and IRF8 dependent transcription is diminished in RIG-I activated cells when TYMP is inhibited. Functional RNAi screen of our TYMP dependent EC genes, we found that a group of 5 genes - Flot1, Ccl5, Vars2, Samd9l and Ube2l6 are critical for endothelial cell death mediated by RIG-I activation. Our observations identify mechanisms by which RIG-I drives EC dysfunction and define pathways that can be pharmacologically targeted to ameliorate RIG-I induced vascular inflammation.

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Section: Resultsmentioning

confidence: 99%

Thymidine phosphorylase facilitates retinoic acid inducible gene-I induced endothelial dysfunction

et al. 2023

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“…Based on available studies, TYMP participates in the metabolism of chemotherapeutic drugs such as 5-FU and capecitabine, and is associated with chemoresistance, as well possibly assisting in predicting susceptibility to chemotherapeutic drugs (25)(26)(27). TYMP plays a vital role in promoting tumor progression, and overexpression of TP enhanced viability and decreased apoptosis in human cholangiocarcinoma cell lines, as well as promoting angiogenesis in intrahepatic cholangiocarcinoma (28). Furthermore, TYMP itself serves as a therapeutic target in cancers and has been utilized in cancer treatment as a TP inhibitor (13).…”

Section: Discussionmentioning

confidence: 99%

A comprehensive pan-cancer analysis on the immunological role and prognostic value of TYMP in human cancers

Yang¹,

Li²,

Wang³

et al. 2022

Transl Cancer Res TCR

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“…Dapsone in cholangiocarcinoma: IL-8-driven chemotaxis of neutrophils infiltrating cholangiocarcinoma constitutes a trophic function in the growing tumor [91][92][93][94][95][96][97][98][99][100][101]. IL-8 drives angiogenesis, and is elevated in cholangiocarcinoma, where higher levels are associated with shorter survival [102][103][104][105][106][107][108][109][110]. As with other cancers, a higher NLR is strongly associated with shorter survival in cholangiocarcinoma [111].…”

Section: Dapsonementioning

confidence: 99%

“…Pyrimethamine in cholangiocarcinoma: In cholangiocarcinoma, upregulated thymidine phosphorylase also contributes to chemotherapy resistance, and furthers survival [109,[277][278][279]. Thymidine phosphorylase overexpression enhances growth and suppresses apoptosis in human umbilical vein endothelial cells, as well as increasing VEGF, IL-8, and the growth of cholangiocarcinoma cells [109]. STAT3 activation is an identified growth driver in cholangiocarcinoma [280][281][282].…”

Section: Pyrimethaminementioning

confidence: 99%

MDACT: A New Principle of Adjunctive Cancer Treatment Using Combinations of Multiple Repurposed Drugs, with an Example Regimen

Kast¹,

Alfieri

Assi

et al. 2022

Cancers

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In part one of this two-part paper, we present eight principles that we believe must be considered for more effective treatment of the currently incurable cancers. These are addressed by multidrug adjunctive cancer treatment (MDACT), which uses multiple repurposed non-oncology drugs, not primarily to kill malignant cells, but rather to reduce the malignant cells’ growth drives. Previous multidrug regimens have used MDACT principles, e.g., the CUSP9v3 glioblastoma treatment. MDACT is an amalgam of (1) the principle that to be effective in stopping a chain of events leading to an undesired outcome, one must break more than one link; (2) the principle of Palmer et al. of achieving fractional cancer cell killing via multiple drugs with independent mechanisms of action; (3) the principle of shaping versus decisive operations, both being required for successful cancer treatment; (4) an idea adapted from Chow et al., of using multiple cytotoxic medicines at low doses; (5) the idea behind CUSP9v3, using many non-oncology CNS-penetrant drugs from general medical practice, repurposed to block tumor survival paths; (6) the concept from chess that every move creates weaknesses and strengths; (7) the principle of mass—by adding force to a given effort, the chances of achieving the goal increase; and (8) the principle of blocking parallel signaling pathways. Part two gives an example MDACT regimen, gMDACT, which uses six repurposed drugs—celecoxib, dapsone, disulfiram, itraconazole, pyrimethamine, and telmisartan—to interfere with growth-driving elements common to cholangiocarcinoma, colon adenocarcinoma, glioblastoma, and non-small-cell lung cancer. gMDACT is another example of—not a replacement for—previous multidrug regimens already in clinical use, such as CUSP9v3. MDACT regimens are designed as adjuvants to be used with cytotoxic drugs.

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Thymidine phosphorylase promotes angiogenesis and tumour growth in intrahepatic cholangiocarcinoma

Cited by 5 publications

References 40 publications

Thymidine phosphorylase facilitates retinoic acid inducible gene-I induced endothelial dysfunction

Thymidine phosphorylase facilitates retinoic acid inducible gene-I induced endothelial dysfunction

A comprehensive pan-cancer analysis on the immunological role and prognostic value of TYMP in human cancers

MDACT: A New Principle of Adjunctive Cancer Treatment Using Combinations of Multiple Repurposed Drugs, with an Example Regimen

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