Metastasis is the main cause of cancer death. Metastatic foci are derived from tumor cells that detach from the primary tumor and then enter the circulation. Circulating tumor cells (CTCs) are generally associated with a high probability of distant metastasis and a negative prognosis. Most CTCs die in the bloodstream, and only a few cells form metastases. Such metastatic CTCs have a stem-like and hybrid epithelial-mesenchymal phenotype, can avoid immune surveillance, and show increased therapy resistance. Targeting metastatic CTCs and their progenitors in primary tumors and their descendants, particularly disseminated tumor cells, represents an attractive strategy for metastasis prevention. However, current therapeutic strategies mainly target the primary tumor and only indirectly affect metastasis-initiating cells. Here, we consider potential methods for preventing metastasis based on targeting molecular and cellular features of metastatic CTCs, including CTC clusters. Also, we emphasize current knowledge gaps in CTC biology that should be addressed to develop highly effective therapeutics and strategies for metastasis suppression.
The spread of tumor cells throughout the body by traveling through the bloodstream is a critical step in metastasis, which continues to be the main cause of cancer-related death. The detection and analysis of circulating tumor cells (CTCs) is important for understanding the biology of metastasis and the development of antimetastatic therapy. However, the isolation of CTCs is challenging due to their high heterogeneity and low representation in the bloodstream. Different isolation methods have been suggested, but most of them lead to CTC damage. However, viable CTCs are an effective source for developing preclinical models to perform drug screening and model the metastatic cascade. In this review, we summarize the available literature on methods for isolating viable CTCs based on different properties of cells. Particular attention is paid to the importance of in vitro and in vivo models obtained from CTCs. Finally, we emphasize the current limitations in CTC isolation and suggest potential solutions to overcome them.
Background. Cancer of unknown primary (CUP) is a metastatic lesion with diffcult identifcation of the primary tumor site using standard diagnostic approaches. Although the incidence of CUP is not high, this type of cancer often shows a high aggressiveness and therapy resistance and results in poor patient survival. The mechanisms of CUP origin are not clear, and further studies are needed.This study aims to analyze the mutational landscape of CUP and identify specifc genetic alterations.Material and Methods. Whole exome sequencing was used to analyze the mutational landscape of CUP. Results. CUP had single nucleotide variants (SNVs) in the EPHA8 (ephrin receptor) gene. CUP also harbored copy number variations (CNAs) in the ID2, FOXD4, ZMYND11, ZNF596, KIDINS220, LRRN1, GEMIN4, CEP72, TPPP, and MXRA5 genes. According to functional enrichment analysis, these genes are involved in the regulation of transcription, biogenesis of microRNA, cellular cytoskeleton, adhesion, extracellular matrix remodeling, proliferation, apoptosis, and epithelial-mesenchymal transition.Conclusion. Cancer of unknown primary harbors mutations in the genes that regulate different biological processes particularly cell motility.
Cancers are one of the leading causes of mortality in the world. Cellular and physiological mechanisms of cancer development remain not well defined. In vivo models are an attractive approach for understanding of cancer origin and progression. This review presents current state of experimental in vivo systems including syngeneic models, patient-derived xenografts (PDX), cell line-derived xenografts (CDX) and various animals – humanized and genetically engineered models (GEM). These models provide opportunities for developing patients’ avatars, lifetime visualization of tumor migration and invasion at the organism level, and the evaluation of new therapeutic methods aimed at primary tumors, metastases, and cancer prevention. We also discuss the problems of choosing the optimal model and potential solutions for their overcoming.
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