News Update on Tumor Metastasis Research: May – 2019
Exosomes play roles in sequential processes of tumor metastasis
Overwhelming evidence demonstrates that exosomes, a series of biologically functional small vesicles of endocytic origin carrying a variety of active constituents, especially tumor‐derived exosomes, contribute to tumor progression and metastasis. This review focuses on the specific multifaceted roles of exosomes in affecting sequenced four crucial processes of metastasis, through which cancer cells spread from primary to secondary organs and finally form macroscopic metastatic lesions. First, exosomes modulate the primary tumor sites to assist cancer growth and dissemination. In this part, five main biological events are reviewed, including the transfer of oncogenic constituents, the recruitment and activation of fibroblasts, the induction of angiogenesis, immunosuppression and epithelial‐mesenchymal transition (EMT) promotion. In Step 2, we list two recently disclosed mechanisms during the organ‐specific homing process: the exosomal integrin model and exosomal epidermal growth factor receptor (EGFR)/miR‐26/hepatocyte growth factor (HGF) model. Subsequently, Step 3 focuses on the interactions between exosomes and pre‐metastatic niche, in which we highlight the specific functions of exosomes in angiogenesis, lymphangiogenesis, immune modulation and metabolic, epigenetic and stromal reprogramming of pre‐metastatic niche. Finally, we summarize the mechanisms of exosomes in helping the metastatic circulating tumor cells escape from immunologic surveillance, survive in the blood circulation and proliferate in host organs. 
FLI1 Exonic Circular RNAs as a Novel Oncogenic Driver to Promote Tumor Metastasis in Small Cell Lung Cancer
Purpose: The aberrantly upregulated Friend leukemia virus integration 1 (FLI1) is closely correlated with the malignant phenotype of small cell lung cancer (SCLC). It is interesting to note that the CRISPR gene knockout by Cas9 gRNAs that target the FLI1 coding region and the posttranscriptional knockdown by shRNAs that target the 3′ region of FLI1 mRNA yielded distinct antimetastasis effects in SCLC cells. This study attempts to examine if FLI1 exonic circular RNAs (FECR) function as a new malignant driver that determines the metastatic phenotype in SCLC.
Experimental Design: The clinical relevance of FECRs was examined in 56 primary SCLC tissues and 50 non–small cell lung cancer (NSCLC) tissues. The prognostic value of FECRs was examined by measuring serum exosomal FECRs in a longitudinal cohort of patients with SCLC. The oncogenic activity of FECRs was investigated in both SCLC cell lines and animal xenograft studies. Finally, we explored the molecular mechanisms underlying these noncoding RNAs as a malignant driver.
Results: Therapeutic comparison of CRISPR Cas9 knockout and shRNA knockdown of FLI1identified FECRs as a new noncanonical malignant driver in SCLC. Using RNA FISH and quantitative PCR, we found that FECR1 (exons 4-2-3) and FECR2 (exons 5-2-3-4) were aberrantly upregulated in SCLC tissues (P < 0.0001), and was positively associated with lymph node metastasis (P < 0.01). Notably, serum exosomal FECR1 was associated with poor survival (P = 0.038) and clinical response to chemotherapy. Silencing of FECRs significantly inhibited the migration in two highly aggressive SCLC cell lines and reduced tumor metastasis in vivo. Mechanistically, we uncovered that FECRs sequestered and subsequently inactivated tumor suppressor miR584-3p, leading to the activation of the Rho Associated Coiled-Coil Containing Protein Kinase 1 gene (ROCK1).
Conclusions: This study identifies FLI1 exonic circular RNAs as a new oncogenic driver that promotes tumor metastasis through the miR584–ROCK1 pathway. Importantly, serum exosomal FECR1 may serve as a promising biomarker to track disease progression of SCLC. 
Loss of exosomal miR‐148b from cancer‐associated fibroblasts promotes endometrial cancer cell invasion and cancer metastasis
Cancer‐associated fibroblasts (CAFs) play crucial roles in tumor progression, given the dependence of cancer cells on stromal support. Therefore, understanding how CAFs communicate with endometrial cancer cell in tumor environment is important for endometrial cancer therapy. Exosomes, which contain proteins and noncoding RNA, are identified as an important mediator of cell–cell communication. However, the function of exosomes in endometrial cancer metastasis remains poorly understood. In the current study we found that CAF‐derived exosomes significantly promoted endometrial cancer cell invasion comparing to those from normal fibroblasts (NFs). We identified a significant decrease of miR‐148b in CAFs and CAFs‐derived exosomes. By exogenously transfect microRNAs, we demonstrated that miR‐148b could be transferred from CAFs to endometrial cancer cell through exosomes. In vitro and in vivo studies further revealed that miR‐148b functioned as a tumor suppressor by directly binding to its downstream target gene, DNMT1 to suppress endometrial cancer metastasis. In endometrial cancer DNMT1 presented a potential role in enhancing cancer cell metastasis by inducing epithelial–mesenchymal transition (EMT). Therefore, downregulated miR‐148b induced EMT of endometrial cancer cell as a result of relieving the suppression of DNMT1. Taken together, these results suggest that CAFs‐mediated endometrial cancer progression is partially related to the loss of miR‐148b in the exosomes of CAFs and promoting the transfer of stromal cell‐derived miR‐148b might be a potential treatment to prevent endometrial cancer progression. 
Ribosome biogenesis during cell cycle arrest fuels EMT in development and disease
Ribosome biogenesis is a canonical hallmark of cell growth and proliferation. Here we show that execution of Epithelial-to-Mesenchymal Transition (EMT), a migratory cellular program associated with development and tumor metastasis, is fueled by upregulation of ribosome biogenesis during G1/S arrest. This unexpected EMT feature is independent of species and initiating signal, and is accompanied by release of the repressive nucleolar chromatin remodeling complex (NoRC) from rDNA, together with recruitment of the EMT-driving transcription factor Snai1 (Snail1), RNA Polymerase I (Pol I) and the Upstream Binding Factor (UBF). EMT-associated ribosome biogenesis is also coincident with increased nucleolar recruitment of Rictor, an essential component of the EMT-promoting mammalian target of rapamycin complex 2 (mTORC2). Inhibition of rRNA synthesis in vivo differentiates primary tumors to a benign, Estrogen Receptor-alpha (ERα) positive, Rictor-negative phenotype and reduces metastasis. These findings implicate the EMT-associated ribosome biogenesis program with cellular plasticity, de-differentiation, cancer progression and metastatic disease.
Incidence of Multiple Mammary Tumors and Fibroadenoma in Pathological Study of Udder Affections in Camel (Camelus dromedarius)
Aims of the Study: To investigate the general histopathological pictures found in the udder tissue of camel (Camelus dromedarius) with emphasis on different types of tumors.
Place and Duration of Study: The study was undertaken in the Department of Pathology, Central Veterinary Research Laboratory, Ministry of Animal Resource and Fisheries, Khartoum, Sudan in 2009.
Study Design: 150 samples of camel udder tissues were obtained from Tumbool abattoir in Al-Gazeera State, gross and histopathological pictures were studied.
Methodology: The macroscopic pictures of samples were reviewed and described, then histopathological lesions were studied using H&E stain. Lastly immunohistochemical staining was done using estrogen and progesterone antibodies in one sample showing mixed tumors.
Results: Out of 150 samples studied, 45(30%) showed neoplastic masses, 23(51.11%) of them were benign and 22(48.89%) were malignant. Different pathological pictures were reported, but only one showed multiple mammary neoplasms contain papillary carcinoma and fibroadenoma.
Conclusion: Mammary tumors were detected for the first time in Sudanese camel and completely confirmed by using histopathological methods. 
 Li, K., Chen, Y., Li, A., Tan, C. and Liu, X., 2019. Exosomes play roles in sequential processes of tumor metastasis. International journal of cancer, 144(7), pp.1486-1495. (Web Link)
 Li, L., Li, W., Chen, N., Zhao, H., Xu, G., Zhao, Y., Pan, X., Zhang, X., Zhou, L., Yu, D. and Li, A., 2019. FLI1 exonic circular RNAs as a novel oncogenic driver to promote tumor metastasis in small cell lung cancer. Clinical Cancer Research, 25(4), pp.1302-1317. (Web Link)
 Li, B.L., Lu, W., Qu, J.J., Ye, L., Du, G.Q. and Wan, X.P., 2019. Loss of exosomal miR‐148b from cancer‐associated fibroblasts promotes endometrial cancer cell invasion and cancer metastasis. Journal of cellular physiology, 234(3), pp.2943-2953. (Web Link)
 Ribosome biogenesis during cell cycle arrest fuels EMT in development and disease
Nature Communicationsvolume 10, Article number: 2110 (2019) (Web Link)
 M. Abeer, A., M. Zakia, A., A. Muna, E. and A. Afaf, E. (2016) “Incidence of Multiple Mammary Tumors and Fibroadenoma in Pathological Study of Udder Affections in Camel (Camelus dromedarius)”, Journal of Cancer and Tumor International, 4(1), pp. 1-7. doi: 10.9734/JCTI/2016/24542. (Web Link)