Angiogenesis in cervical cancer is mediated by HeLa metabolites through endothelial cell tissue kallikrein

Naidoo, Strinivasen; Raidoo, Deshandra M.

doi:10.3892/or_00000436

Cited by 5 publications

(4 citation statements)

References 37 publications

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“…With the recent discovery of all of the fifteen members of the KLK family, increasing evidence has indicated that KLKs may play pivotal roles in breast cancer progression and metastasis (Table 4, Figure 1,2). 6,63–65 In normal breast tissue, all fifteen KLKs have been identified, either at the mRNA and/or the protein level 23,66. KLK15 mRNA is not expressed by normal breast tissue, low to moderate mRNA levels are detected for KLK2–5, 9, 12 and 13 , high ones for KLK1, 6–8, 10, 11 and 14.…”

Section: Klk Expression In Breast Cancermentioning

confidence: 99%

Emerging clinical importance of the cancer biomarkers kallikrein-related peptidases (KLK) in female and male reproductive organ malignancies

Schmitt¹,

Magdolen²,

Yang³

et al. 2013

Radiology and Oncology

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BackgroundTumor tissue-associated KLKs (kallikrein-related peptidases) are clinically important biomarkers that may allow prognosis of the cancer disease and/or prediction of response/failure of cancer patients to cancer-directed drugs. Regarding the female/male reproductive tract, remarkably, all of the fifteen KLKs are expressed in the normal prostate, breast, cervix uteri, and the testis, whereas the uterus/endometrium and the ovary are expressing a limited number of KLKs only.ConclusionsMost of the information regarding elevated expression of KLKs in tumor-affected organs is available for ovarian cancer; depicting them as valuable biomarkers in the cancerous phenotype. In contrast, for breast cancer, a series of KLKs was found to be downregulated. However, in breast cancer, KLK4 is elevated which is also true for ovarian and prostate cancer. In such cases, selective synthetic KLK inhibitors that aim at blocking the proteolytic activities of certain KLKs may serve as future candidate therapeutic drugs to interfere with tumor progression and metastasis.

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Section: Klk Expression In Breast Cancermentioning

confidence: 99%

Emerging clinical importance of the cancer biomarkers kallikrein-related peptidases (KLK) in female and male reproductive organ malignancies

Schmitt¹,

Magdolen²,

Yang³

et al. 2013

Radiology and Oncology

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“…61,62 While communication between cervical cancer cells and endothelial cells has been investigated in vitro, all of these studies have been done with either conditioned media, which does not allow for crosstalk, or transwell assays, which do not enable juxtracrine signaling or observation of 3D behavior. [63][64][65] Therefore, this work is the first to evaluate the role of cervical cancer-endothelial cell crosstalk on cervical cancer invasion or microvessel formation in an in vitro model. The results of our DOE revealed a complex nonlinear relationship between fibrin and collagen concentrations in the bottom hydrogel on both endothelial cell and cervical cancer behavior.…”

Section: Discussionmentioning

confidence: 99%

Engineering High Throughput Screening Platforms of Cervical Cancer

Cadena

Buchanan

Harris

et al. 2022

Preprint

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There is a critical need for complex multicellular three-dimensional physiomimetic models of cancer that can interface with high throughput drug screening methods to assess anti-metastatic and anti-angiogenic drug efficacy in a rapid yet high content manner. We report a multilayer multicellular platform of human cervical cancer cell lines and primary human microvascular endothelial cells that incorporates critical biophysical and extracellular matrix cues, interfaces with standard high throughput drug screening methods, and can evaluate cervical cancer invasion and endothelial microvessel formation over time. Through the use of Design of Experiments statistical optimization, we identified the specific concentrations of collagen I, fibrinogen, fibronectin, GelMA, and PEGDA in each hydrogel layer that maximized cervical cancer invasion and endothelial microvessel length simultaneously. We then validated the optimized platform and assessed the viscoelastic properties of the composite hydrogels as well as their individual constituents. Finally, using this optimized platform, we conducted a targeted drug screen of four clinically relevant drugs on two cervical cancer cell lines. From these data we identified each of the cervical cancer cell lines (SiHa and Ca Ski) as either responsive or refractive to Paclitaxel, Dasitinib, Dovitinib, or Pazopanib. Overall, we developed a phenotypic drug screening platform of cervical cancer that captures cell behavior present in the cervical cancer tumor microenvironment, captures patient to patient variability, and integrates with standard high throughput high content drug screening methods. This work provides a valuable platform that can be used to screen large compound libraries for mechanistic studies, drug discovery, and precision oncology for cervical cancer patients.

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“…Endothelial cell proliferation is an integral component of pro-angiogenic response [ 59 ]. HeLa cells are known to release serine protease tissue Kallikrein that induced endothelial cell proliferation [ 60 ]. Incidentally, multiplex proximity extension assays on exosomal proteome showed presence of Kallikrein in human milk and prostate cancer exosomes [ 61 ], which suggests that pro-angiogenic proteins like Kallikrein may be directly exported through exosomes.…”

Section: Discussionmentioning

confidence: 99%

Exosomes from cervical cancer cells facilitate pro-angiogenic endothelial reconditioning through transfer of Hedgehog–GLI signaling components

et al. 2021

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Background Angiogenic switch is a hallmark feature of transition from low-grade to high-grade cervical intraepithelial neoplasia (CIN) in cervical cancer progression. Therefore, early events leading to locally-advanced cervical metastatic lesions demand a greater understanding of the underlying mechanisms. Recent leads indicate the role of tumor-derived exosomes in altering the functions of endothelial cells in cervical cancer, which needs further investigation. Methods Exosomes isolated from cervical cancer cell lines were assessed for their angiogenic effect on the human umbilical vein endothelial cells (HUVEC) using tube formation and wound healing assay. The exosomal uptake by HUVEC cells was monitored using PKH-67 labelling followed by fluorescence microscopy. Alterations in Hh-GLI signaling components, PTCH1 and GLI1, in HUVEC were measured by immunoblotting. Changes in angiogenesis-related transcripts of vascular endothelial growth factor VEGF-A, VEGF-B, VEGFR2 and angiopoietin-1, angiopoietin-2, osteopontin were measured in exosome-treated HUVEC and in the exosomal RNA by RT-PCR. Results Enhanced tube formation, with an increased number of nodes and branching was observed in HUVEC’s treated with exosomes derived from different cervical cancer cell lines. HPV-positive (SiHa and HeLa) cells’ exosomes were more angiogenic. Exosome-treated HUVEC showed increased migration rate. PKH-67 labelled exosomes were found internalized in HUVEC. A high level of PTCH1 protein was detected in the exosome—treated endothelial cells. Subsequent RT-PCR analysis showed increased transcripts of Hh-GLI downstream target genes VEGF-A, VEGFR2, angiopoietin-2, and decreased expression of VEGF-B, and angiopoietin-1, suggestive of active Hh-GLI signaling. These effects were more pronounced in HUVEC’s treated with exosomes of HPV-positive cells. However, these effects were independent of tumor-derived VEGF-A as exosomal cargo lacked VEGF-A transcripts or proteins. Conclusion Overall, the data showed cervical cancer exosomes promote pro-angiogenic response in endothelial cells via upregulation of Hh-GLI signaling and modulate downstream angiogenesis-related target genes. The study provides a novel exosome-mediated mechanism potentially favoring cervical angiogenesis and thus identifies the exosomes as potential pharmacological targets against locally-advanced metastatic cervical lesions. Graphic abstract

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Angiogenesis in cervical cancer is mediated by HeLa metabolites through endothelial cell tissue kallikrein

Abstract: Abstract. High vascularity correlates with poor clinical outcome in cancer of the uterine cervix. We investigated whether human cervical cancer cell (HeLa) metabolites influenced endothelial cell proliferation through the serine protease, tissue kallikrein.

Cited by 5 publications

References 37 publications

Emerging clinical importance of the cancer biomarkers kallikrein-related peptidases (KLK) in female and male reproductive organ malignancies

Emerging clinical importance of the cancer biomarkers kallikrein-related peptidases (KLK) in female and male reproductive organ malignancies

Engineering High Throughput Screening Platforms of Cervical Cancer

Exosomes from cervical cancer cells facilitate pro-angiogenic endothelial reconditioning through transfer of Hedgehog–GLI signaling components

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