High accumulation of hyaluronan (HA) in the tumor microenvironment leads to an increase in the interstitial pressure and reduction perfusion of drugs. Furthermore, high molecular-weight (HMW)-HA suppresses M1 macrophage polarization, enhances M2 polarization, and induces immunosuppression. Hyaluronidase treatment have attempted to decrease the quantity of HA in tumors. However, hyaluronidase-driven HA degradation driven accelerates tumor cell metastasis, which is a major cause of mortality in cancer patients. Thus, we designed a novel exosome-based drug delivery system (DDS), named Exos-PH20-FA, using genetic engineering to express human hyaluronidase (PH20) and self-assembly techniques to modify the exosomes with folic acid (FA). Our results show that Exos-PH20-FA degraded HMW-HA to low-molecular-weight (LMW)-HA. Moreover, LMW-HA polarized macrophages to the M1 phenotype and reduced the number of relevant immunosuppressive immunocytes which changed the immune microenvironment from an immunosuppressive to immunosupportive phenotype. Furthermore, we demonstrated Exos-PH20-FA directly reduced hyaluronidase-induced metastasis of tumor cells. This tumor treatment also allowed an enhanced delivery of chemotherapy by tumor-targeting effect with FA modification. Our findings indicate that Exos-PH20-FA improves tumor treatment efficiency and reduces the side effects of hyaluronidase treatment, namely tumor cell metastasis. This all-in-one exosome-based HA targeting DDS maybe a promising treatment that yields more efficient and safer results.

Cancer cachexia is a metabolic disorder characterized by skeletal muscle wasting and white adipose tissue browning. Specific functions of several hormones, growth factors, and cytokines derived from tumors can trigger cachexia. Moreover, adipose tissue lipolysis might explain weight loss that occurs owing to cachexia. Extracellular vesicles (EVs) are involved in intercellular communication. However, whether EVs participate in lipolysis induced by cancer cachexia has not been thoroughly investigated. Using Lewis lung carcinoma (LLC) cell culture, we tested whether LLC cell-derived EVs can induce lipolysis in 3T3-L1 adipocytes. EVs derived from LLC cells were isolated and characterized biochemically and biophysically. Western blotting and glycerol assay were used to study lipolysis. LLC cell-derived EVs induced lipolysis in vivo and vitro. EVs fused directly with target 3T3-L1 adipocytes and transferred parathyroid hormone-related protein (PTHrP), activating the PKA signaling pathway in 3T3-L1 adipocytes. Blocking PTHrP activity in LLC-EVs using a neutralizing antibody and by knocking down PTHR expression prevented lipolysis in adipocytes. Inhibiting the PKA signaling pathway also prevents the lipolytic effects of EVs. In vivo, suppression of LLC-EVs release by knocking down Rab27A alleviated white adipose tissue browning and lipolysis. Our data showed that LLC cell-derived EVs induced adipocyte lipolysis via the extracellular PTHrP-mediated PKA pathway. Our data demonstrate that LLC-EVs induce lipolysis in vitro and vivo by delivering PTHrP, which interacts with PTHR. The lipolytic effect of LLC-EVs was abrogated by PTHR knockdown and treatment with a neutralizing anti-PTHrP antibody. Together, these data show that LLC-EV-induced lipolysis is mediated by extracellular PTHrP. These findings suggest a novel mechanism of lipid droplet loss and identify a potential therapeutic strategy for cancer cachexia.

Background:Golgi phosphoprotein 3 (GOLPH3) has been reported to be involved in the development of several human cancers. The present study was conducted to investigate the expression of GOLPH3 and its prognostic significance in renal cell carcinoma (RCC). Meanwhile, the function of GOLPH3 in human RCC was further investigated in cell culture models.Methods:Expression of GOLPH3 was examined in 43 fresh RCC tissues and paired adjacent normal renal tissues by real-time quantitative PCR and western blotting. Immunohistochemistry for GOLPH3 was performed on additional 218 RCC tissues. The clinical significance of GOLPH3 expression was analysed. Downregulation of GOLPH3 was performed using small-interfering RNA (siRNA) in Caki-1 and 786-O cells with high abundance of GOLPH3, and the effects of GOLPH3 silencing on cell proliferation, migration, invasion in vitro, and tumour growth in vivo were evaluated.Results:Expression of GOLPH3 was upregulated in the majority of the RCC clinical tissue specimens at both mRNA and protein levels. Clinicopathological analysis showed that GOLPH3 expression was significantly correlated with T stage (P<0.001), lymph-node status (P=0.003), distant metastasis (P<0.001), tumour-node-metastasis (TNM) stage (P<0.001), and Fuhman grade (P=0.001). Expression of GOLPH3 was inversely correlated with both overall and recurrence-free survival of RCC patients. Multivariate analysis showed that GOLPH3 expression was an independent prognostic indicator for patient's survival. Knockdown of the GOLPH3 expression reduced cell proliferation, anchorage-independent growth, migration, invasion, and tumour growth in xenograft model mice.Conclusions:These results suggest that GOLPH3 expression is likely to have important roles in RCC development and progression, and that GOLPH3 is a prognostic biomarker and a promising therapeutic target for RCC.

Background: Stratification of tumors is necessary to achieve better clinical outcomes. Hepatocellular carcinoma (HCC) is commonly associated with mutation of the TP53 gene and heterogeneity in immune cell content. However, TP53 mutation-associated immunotype of HCC has not been reported yet. This study aimed to identify the TP53 mutation-associated immunotype in HCC. Methods:The mutation annotation format (MAF) document, mRNA expression data, and clinical data of HCC patients were downloaded from the publicly available The Cancer Genome Atlas (TCGA) data portal.Data from 332 HCC patients were analyzed in this study. Infiltrating immune cells were evaluated by the well-known CIBERSORT method. Additional mutation data of HCC patients were downloaded from the Catalogue of Somatic Mutations in Cancer (COSMIC) database. Results:The TP53 gene harbored the highest frequency of mutations in HCC patients. Consequently, five lethal features, including TP53 mutations, were screened by least absolute shrinkage and selector operation (LASSO)-COX regression, according to TP53 mutations and 22 infiltrating immune cells. Two distinct subgroups of HCC were identified, namely, immunotypes A and B. Furthermore, the expression levels of co-inhibitory immune checkpoints were significantly upregulated, and the gene ontology (GO) terms or pathways to boost immune responses were found to be inhibited in the immunotype B subgroup compared to that in the immunotype A subgroup. Finally, we proved immunotype to be an independent adverse prognostic factor that contributed to improvement in the predictive accuracy of the immunotype-based model and helped in avoiding excessive medical treatment.Conclusions: Two distinct immunotypes of HCC, in terms of prognosis, phenotype, and function, were identified and the traditional understanding of intratumoralCD8 + T cells was subverted. Moreover, the identified immunotypes contributed to improving the predictive accuracy of the immunotype-based model and helped in avoiding excessive medical treatment in some HCC patients.

Substantial research attention has been directed at exploring the mechanisms and treatment of renal cell carcinoma (RCC). Indeed, the association between inflammation and tumor phenotypes has been at the center of cancer research. Concomitant with research on the inflammation response and inflammatory molecules involved in RCC, new breakthroughs have emerged. A large body of knowledge now shows that treatments targeting inflammation and immunity in RCC provide substantial clinical benefits. Adequate analysis and a better understanding of the mechanisms of inflammatory factors in the occurrence and progression of RCC are highly desirable. Currently, numerous RCC treatments targeted at inflammation and immunotherapy are available. The current review describes in detail the link between inflammation and RCC.