Cathepsin C promotes colorectal cancer metastasis by regulating immune escape through upregulating CSF1.

Since metastasis remains the primary reason for colorectal cancer (CRC) associated death, a better understanding of the molecular mechanism underlying CRC metastasis is urgently needed. Here, we elucidated the role of Cathepsin C (CTSC) in promoting CRC metastasis. The expression of CTSC was detected by real-time PCR and immunohistochemistry in the human CRC cohort. The metastatic capacities of CTSC-mediated metastasis were analyzed by in vivo metastasis model. Elevated CSTC expression was positively associated with tumor differentiation, tumor invasion, lymph node metastasis, and AJCC stage and indicated poor prognosis in human CRC. CTSC overexpression in CRC cells promoted myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) recruitment by the CSF1/CSF1R axis. In contrast, the knockdown of CSF1 reduced CTSC-mediated MDSCs and TAMs infiltration and CRC metastasis. Depletion of either MDSCs or TAMs decreased CTSC-mediated CRC metastasis. In human CRC tissues, CTSC expression was positively associated with intratumoral MDSCs and TAMs infiltration. Furthermore, the combination of CTSC inhibitor AZD7986 and anti-PD-L1 antibody blocked CTSC-induced CRC metastasis. CTSC overexpression promoted MDSCs and TAMs infiltration by CSF1/CSF1R axis. Interruption of this oncogenic loop may provide a promising treatment strategy for inhibiting CTSC-driven CRC metastasis.

Influence of tube voltage, tube current and newer iterative reconstruction algorithms in CT perfusion imaging in rabbit liver VX2 tumors.

PURPOSE: We aimed to explore the influence of tube voltage, current and iterative reconstruction (IR) in computed tomography perfusion imaging (CTPI) and to compare CTPI parameters with microvessel density (MVD). METHODS: Hepatic CTPI with three CTPI protocols (protocol A, tube voltage/current 80 kV/40 mAs; protocol B, tube voltage/current 80 kV/80 mAs; protocol C: tube voltage/current 100 kV/80 mAs) were performed in 25 rabbit liver VX2 tumor models, and filtered back projection (FBP) and IR were used for reconstruction of raw data. Hepatic arterial perfusion (HAP), hepatic portal perfusion (HPP), total perfusion (TP), hepatic arterial perfusion index (HPI), blood flow (BF) and blood volume (BV) of VX2 tumor and normal hepatic parenchyma were measured. Image noise, signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were quantified and radiation dose was recorded. MVD was counted using CD34 stain and compared with CTPI parameters. RESULTS: The highest radiation dose was found in protocol C, followed by protocols B and A. IR lowered image noise and improved SNR and CNR in all three protocols. There was no statistical difference between HAP, HPP, TP, HPI, BF and BV of VX2 tumor and normal hepatic parenchyma among the three protocols (P > 0.05) with FBP or IR reconstruction, and no statistical difference between IR and FBP reconstruction (P > 0.05) in either protocol. MVD had a positive linear correlation with HAP, TP, BF, with best correlation observed with HAP; MVD of VX2 tumor showed no or poor correlation with HPI and BV. CONCLUSION: CTPI parameters are not affected by tube voltage, current or reconstruction algorithm; HAP can best reflect MVD, but no correlation exists between BV and MVD.

Comparison of microvascular perfusion evaluation among IVIM-DWI, CT perfusion imaging and histological microvessel density in rabbit liver VX2 tumors.

OBJECT: To explore microcirculation features with intravoxel incoherent motion (IVIM) and to compare IVIM with CT perfusion imaging (CTPI) and microvessel density (MVD). MATERIALS AND METHODS: Hepatic CTPI and IVIM were performed in 16 rabbit liver VX2 tumor models. Hepatic arterial perfusion (HAP), hepatic arterial perfusion index (HPI), Blood flow (BF), and blood volume (BV) from CTPI were measured. Apparent diffusion coefficient (ADC), true diffusion coefficient (D), perfusion fraction (f), and pseudo-diffusion coefficient (D*) from IVIM were measured. MVD was counted with CD34 stain. The microcirculation features with IVIM were compared with CTPI parameters and MVD. RESULTS: Strong linear correlations were found between D value (0.89±0.21×10-3mm2/s) and HAP (15.83±6.97ml/min/100mg) (r=0.755, P=0.001) and between f value (12.64±6.66%) and BV (9.74±5.04ml/100mg) (r=0.693, P=0.004). Moderate linear correlations were observed between ADC (1.07±0.32×10-3mm2/s) and HAP (r=0.538, P=0.039), respectively; and between D value and MVD (9.31±2.57 vessels at 400×magnification) (r=0.509, P=0.044). No correlations were found between D* (119.90±37.67×10-3mm2/s) and HAP, HPI (68.34±12.91%), BF (4.95±2.16ml/min/100mg), BV. CONCLUSION: IVIM parameters can characterize microcirculation to certain extent and separate it from pure water molecular diffusion. There is fair correlation between D or ADC value and CTPI parameters or MVD, but no correlation between D* or f value and CTPI parameters or MVD except f value and BV, which is still unclear and need further clinical studies to validate.

Individualized reduction of radiation dose with a chest circumference-adapted technique and iterative reconstructions in 256-slice retrospective and prospective ECG-triggered computed tomography coronary angiography.

PURPOSE: To assess the impact of chest circumference (CC)-adjusted tube current and iterative reconstructions (iDose) on individualized radiation dose reduction and image quality (IQ) in ECG-triggered computed tomography coronary angiography (CTCA). MATERIALS AND METHODS: A total of 102 patients underwent retrospectively ECG-triggered CTCA utilizing CC-adapted tube current [mAs=1000×(0.051×CC-23.765)/900] and filtered back projection (FBP) reconstruction (group A). On the basis of the CC-adjusted tube current technique, 54 patients (group B) underwent retrospective ECG-triggered CTCA with a 20% mAs reduction compared with group A and 90 patients (group C) underwent prospective ECG-triggered CTCA with an 80% mAs reduction compared with group A; both groups B and C were reconstructed with FBP and iDose. Subjective IQ was assessed, and image noise, signal-to-noise, and contrast-to-noise ratios (SNR and CNR) were quantified. RESULTS: Patients in group A had the highest radiation dose, followed by group B and group C. iDose provided decreased image noise and increased SNR and CNR, as did subjective IQ. The image noise was higher and SNR and CNR in group B were obviously lower than those in group A with FBP, but in group B, iDose4 increased the mean objective IQ. There was no difference between group B with iDose and group A with FBP, as was the case with subjective IQ. CONCLUSION: The combination of a CC-adapted technique, prospective triggering, and partial iterative reconstruction techniques reduces the radiation dose significantly, without significant degradation of IQ.