Oncolytic adenoviruses are a promising treatment alternative for many advanced cancers, including colorectal cancer. However, clinical trials have demonstrated that single-agent therapy in advanced tumor masses is rarely curative. Poor spreading of the virus through tumor tissue is one of the major issues limiting efficacy. As oncolytic viruses kill preferentially cancer cells, high extracellular matrix (ECM) content constitutes potential barriers for viral penetration within tumors. In this study, the ECM-degrading proteases relaxin, hyaluronidase, elastase and macrophage metalloelastase (MME) were tested for their antitumor efficacy alone and in combination with oncolytic adenovirus. MME improved the overall antitumor efficacy of oncolytic adenovirus in subcutaneous HCT116 xenografts. In a liver metastatic colorectal cancer model, intra-tumoral treatment of primary tumors from HT29 cells with MME monotherapy or with oncolytic adenovirus inhibited tumor growth. Combination therapy showed no increased mortality in comparison with either monotherapy alone. Contradictory results of effects of MME on tumorigenesis and metastasis formation have been reported in the literature. This study demonstrates for the first time in a metastatic animal model that MME, as a monotherapy or in combination with oncolytic virus, does not increase tumor invasiveness. Co-administration of MME and oncolytic adenovirus may be a suitable approach for further optimization aiming at clinical applications for metastatic colorectal cancer.
Introduction/Objective
Renal cell carcinomas (RCCs) are well-vascularized tumors. Although clear cell RCC (ccRCC) shows a characteristic vascular network, in some cases may show overlapping features with other RCCs. Microvessel density (MVD) and architectural vascular arrangement in RCC have been characterized using CD31 and CD34 immunohistochemical (IHC) stains. To date, no studies have evaluated the vascular distribution in ccRCC compared to clear cell papillary RCC (ccpRCC). We aimed to identify potential differences in MVD, vascular pattern architecture and extent in ccRCC and ccpRCC.
Methods
Fifteen cases of ccRCC and 15 cases of ccpRCC were included in the study. ERG IHC stain and Bioquant Osteo 2019 Imaging Analysis Software were used to evaluate MVD in 12 cases (6 ccRCC, 6 ccpRCC). CD34 was used to evaluate architectural vascular pattern and its extent (% of tumor) in all cases. Mann–Whitney U test in STATA version 16.0 was used for statistical analysis.
Results
MVD means were 30.64 (CI: 17.9-43.29) in ccRCC and 29.2 (CI: 17.82-40.57) in ccpRCC. CD34 highlighted 4 distinct vascular patterns: lacunae, pseudoacinar, Golgi-like and scattered. The extent of patterns ranged from 0% to 90%. Heterogeneous distribution of different vascular patterns was found in both RCC groups. Although lacunae pattern was present in all RCC cases, pseudoacinar (100.0% vs 31.0%), Golgi-like (53.8% vs 100%) and scattered (53.8% vs 38.0%) patterns showed different distribution in ccRCC vs ccpRCC, respectively. Lacunae+pseudoacinar was the most frequent combination in all ccRCCs; lacunae+Golgi-like was identified in 77% of ccpRCCs. Pseudoacinar was the most extensive pattern in ccRCCs, meanwhile Golgi-like was the predominant pattern in ccpRCCs (p value<0.05).
Conclusion
There was no difference in MVD between ccRCC and ccpRCC. However, the extent of vascular patterns pseudoacinar and Golgi-like was significantly different between ccRCC and ccpRCC. Distinct architectural vascular arrangement could help discriminate these entities.
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