Saturation transfer properties of tumour xenografts derived from prostate cancer cell lines 22Rv1 and DU145

Histopathology is currently the most reliable tool in assessing the aggressiveness and prognosis of solid tumours. However, developing non-invasive modalities for tumour evaluation remains crucial due to the side effects and complications caused by biopsy procedures. In this study, saturation transfer MRI was used to investigate the microstructural and metabolic properties of tumour xenografts in mice derived from the prostate cancer cell lines 22Rv1 and DU145, which express different aggressiveness. The magnetization transfer (MT) and chemical exchange saturation transfer (CEST) effects, which are associated with the microstructural and metabolic properties in biological tissue, respectively, were analyzed quantitatively and compared amongst different tumour types and regions. Histopathological staining was performed as a reference. Higher cellular density and metabolism expressed in more aggressive tumours (22Rv1) were associated with larger MT and CEST effects. High collagen content in the necrotic regions might explain their higher MT effects compared to tumour regions.

Multifunctional Nanobubbles Carrying Indocyanine Green and Paclitaxel for Molecular Imaging and the Treatment of Prostate Cancer

Background: Combining ultrasound imaging with photoacoustic imaging provides tissue imaging with high contrast and resolution, thereby enabling rapid, direct measurements and the tracking of tumour growth and metastasis. Moreover, ultrasound-targeted nanobubble destruction (UTND) provides an effective way to deliver drugs, effectively increasing the content of the drug in the tumour area and reducing potential side effects, thereby successfully contributing to the treatment of tumours. Results: In this study, we prepared multifunctional nanobubbles (NBs) carrying indocyanine green (ICG) and paclitaxel (PTX) (ICG-PTX NBs) and studied their applications in ultrasound imaging of prostate cancer as well as their therapeutic effects on prostate cancer when combined with UTND. ICG-PTX NBs were prepared by the mechanical oscillation method. The particle size and zeta potential of the ICG-PTX NBs were 469.5 ± 32.87 nm and -21.70 ± 1.22 mV, respectively. The encapsulation efficiency and drug loading efficiency of ICG were 68% and 6.2%, respectively. In vitro imaging experiments showed that ICG-PTX NBs were highly amenable to multimodal imaging, including ultrasound, photoacoustic and fluorescence imaging, and the imaging effect was positively correlated with their concentration. The imaging effects of tumour xenografts also indicated that ICG-PTX NBs were of good use for multimodal imaging. In experiments testing the growth of PC-3 cells in vitro and tumour xenografts in vivo, the ICG-PTX NBs+US group showed more significant inhibition of cell proliferation and the promotion of cell apoptosis compared to the other groups (P < 0.05). Blood biochemical analysis of the six groups showed that the levels of aspartate aminotransferase (AST), phenylalanine aminotransferase (ALT), serum creatinine (CRE) and blood urea nitrogen (BUN) in the ICG-PTX NBs and the ICG-PTX NBs+US groups were significantly lower than those in the PTX group (P < 0.05). Moreover, H&E staining of tissue sections from vital organs showed no obvious abnormalities in the ICG-PTX NBs and the ICG-PTX NBs+US groups. Conclusions: ICG-PTX NBs can be used as a non-invasive, pro-apoptotic contrast agent that can achieve multimodal imaging, including ultrasound, fluorescence and photoacoustic imaging, and can succeed in the local treatment of prostate cancer providing a potential novel method for integrated research on prostate cancer diagnosis and treatment.

A mouse SWATH-mass spectrometry reference spectral library enables deconvolution of species-specific proteomic alterations in human tumour xenografts

ABSTRACTSWATH-mass spectrometry (MS) enables accurate and reproducible proteomic profiling in multiple model organisms including the mouse. Here, we present a comprehensive mouse reference spectral library (MouseRefSWATH) that permits quantification of up to 10,597 proteins (62.2% of the mouse proteome) by SWATH-MS. We exploit MouseRefSWATH to develop an analytical pipeline for species-specific deconvolution of proteomic alterations in human tumour xenografts (XenoSWATH). This method overcomes the challenge of high sequence similarity between mouse and human proteins, facilitating the study of host microenvironment-tumour interactions from ‘bulk tumour’ measurements. We apply the XenoSWATH pipeline to characterize an intraductal xenograft model of breast ductal carcinoma in situ and uncover complex regulation consistent with stromal reprogramming, where the modulation of cell migration pathways is not restricted to tumour cells but also operates in the mouse stroma upon progression to invasive disease. MouseRefSWATH and XenoSWATH open new opportunities for in-depth and reproducible proteomic assessment to address wide-ranging biological questions involving this important model organism.

A mouse SWATH-MS reference spectral library enables deconvolution of species-specific proteomic alterations in human tumour xenografts

SWATH-mass spectrometry (MS) enables accurate and reproducible proteomic profiling in multiple model organisms including the mouse. Here we present a comprehensive mouse reference spectral library (MouseRefSWATH) that permits quantification of up to 10,597 proteins (62.2% of the mouse proteome) by SWATH-MS. We exploit MouseRefSWATH to develop an analytical pipeline for species-specific deconvolution of proteomic alterations in human tumour xenografts (XenoSWATH). This method overcomes the challenge of high sequence similarity between mouse and human proteins, facilitating the study of host microenvironment-tumour interactions from ‘bulk tumour’ measurements. We apply the XenoSWATH pipeline to characterise an intraductal xenograft model of breast ductal carcinoma in-situ and uncover complex regulation of cell migration pathways that are not restricted to tumour cells but also operate in the mouse stroma upon progression to invasive disease. MouseRefSWATH and XenoSWATH opens new opportunities for in-depth and reproducible proteomic assessment to address wide-ranging biological questions involving this important model organism.

1,4-dihydroxy Quininib Attenuates Growth of Colorectal Cancer Cells and Xenografts and Regulates the TIE-2 Signaling Pathway in Patient Tumours

Colorectal cancer (CRC) is the second leading cause of cancer associated deaths in developed countries. Cancer progression and metastatic spread is reliant on new blood vasculature, or angiogenesis. Tumour-related angiogenesis is regulated by pro- and anti-angiogenic factors secreted from malignant tissue in a stepwise process. Previously we structurally modified the small anti-angiogenic molecule quininib and discovered a more potent anti-angiogenic compound 1, 4 dihydroxy quininib (Q8), an antagonist of cysteinyl leukotriene receptor-1 with VEGF-independent bioactivity. Here, Q8, quininib (Q1) and five structural analogues were assayed for anti-tumorigenic effects in pre-clinical cancer models. Q8 reduced clone formation of the human colorectal cancer cell line HT29-Luc2. Gene silencing of CysLT1 in HT29-Luc2 cells significantly reduced expression of calpain-2. In human ex vivo colorectal cancer tumour explants, Q8 significantly decreased the secretion of both TIE-2 and VCAM-1 expression. In vivo Q8 was well tolerated up to 50 mg/kg by Balb/C mice and significantly more effective at reducing tumour volume in colorectal tumour xenografts compared to the parent drug quininib. In tumour xenografts, Q8 significantly reduced expression of the angiogenic marker calpain-2 in. In summary, we propose Q8 may act on the TIE-2-Angiopoietin signalling pathway to significantly inhibit the process of tumour angiogenesis in colorectal cancer.