Paracellular and transcellular migration of metastatic cells through the cerebral endothelium

The metastatic process has still not been completely elucidated, probably due to insufficient knowledge of the underlying mechanisms. Here, we provide an overview of the current findings that shed light on specific molecular alterations associated with metastasis and present novel concepts in the treatment of the metastatic process. In particular, we discuss novel pharmacological approaches in the clinical setting that target metastatic progression. New insights into the process of metastasis allow optimisation and design of new treatment strategies, especially in view of the fact that metastatic cells share common features with stem cells. Nano- and micro-technologies are herein elaborated in details as a promising therapeutic concept in targeted drug delivery for metastatic cancer. Progression in the field could provide a more efficient way to tackle metastasis and thus bring about advancements in the treatment and management of patients with advanced cancer.

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Inactivation of EMILIN-1 by Proteolysis and Secretion in Small Extracellular Vesicles Favors Melanoma Progression and Metastasis

International Journal of Molecular Sciences ◽

10.3390/ijms22147406 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7406

Author(s):

Ana Amor López ◽

Marina S. Mazariegos ◽

Alessandra Capuano ◽

Pilar Ximénez-Embún ◽

Marta Hergueta-Redondo ◽

...

Keyword(s):

Lymph Node ◽

Lymph Node Metastasis ◽

Cell Viability ◽

Extracellular Vesicles ◽

Primary Tumor ◽

Molecular Mechanisms ◽

Primary Tumor Growth ◽

Node Metastasis ◽

Metastatic Cells ◽

Tumor Growth And Metastasis

Several studies have demonstrated that melanoma-derived extracellular vesicles (EVs) are involved in lymph node metastasis; however, the molecular mechanisms involved are not completely defined. Here, we found that EMILIN-1 is proteolyzed and secreted in small EVs (sEVs) as a novel mechanism to reduce its intracellular levels favoring metastasis in mouse melanoma lymph node metastatic cells. Interestingly, we observed that EMILIN-1 has intrinsic tumor and metastasis suppressive-like properties reducing effective migration, cell viability, primary tumor growth, and metastasis. Overall, our analysis suggests that the inactivation of EMILIN-1 by proteolysis and secretion in sEVs reduce its intrinsic tumor suppressive activities in melanoma favoring tumor progression and metastasis.

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Inhibition of CCL7 derived from Mo-MDSCs prevents metastatic progression from latency in colorectal cancer

Cell Death and Disease ◽

10.1038/s41419-021-03698-5 ◽

2021 ◽

Vol 12 (5) ◽

Author(s):

Xiaoli Ren ◽

Jianbiao Xiao ◽

Wanning Zhang ◽

Feifei Wang ◽

Yongrong Yan ◽

...

Keyword(s):

Colorectal Cancer ◽

Suppressor Cells ◽

Metastatic Progression ◽

Ht29 Cells ◽

Metastatic Cells ◽

Long Time ◽

Mice Liver ◽

Short Time ◽

Related Proteins

AbstractIn colorectal cancer (CRC), overt metastases often appear after years of latency. But the signals that cause micro-metastatic cells to remain indolent, thereby enabling them to survive for extended periods of time, are unclear. Immunofluorescence and co-immunoprecipitation assays were used to explore the co-localization of CCL7 and CCR2. Immunohistochemical (IHC) assays were employed to detect the characters of metastatic HT29 cells in mice liver. Flow cytometry assays were performed to detect the immune cells. Bruberin vivo MS FX Pro Imager was used to observe the liver metastasis of CRC in mice. Quantitative real-time PCR (qRT-PCR) and western blot were employed to detect the expressions of related proteins. Trace RNA sequencing was employed to identify differentially expressed genes in MDSCs from liver micro-M and macro-M of CRC in mice. Here, we firstly constructed the vitro dormant cell models and metastatic dormant animal models of colorectal cancer. Then we found that myeloid-derived suppressor cells (MDSCs) were increased significantly from liver micro-metastases to macro-metastases of CRC in mice. Moreover, monocytic MDSCs (Mo-MDSC) significantly promoted the dormant activation of micro-metastatic cells compared to polymorphonuclear MDSCs (PMN-MDSC). Mechanistically, CCL7 secreted by Mo-MDSCs bound with membrane protein CCR2 of micro-metastatic cells and then stimulated the JAK/STAT3 pathway to activate the dormant cells. Low-dose administration of CCL7 and MDSCs inhibitors in vivo could significantly maintain the CRC metastatic cells dormant status for a long time to reduce metastasis or recurrence after radical operation. Clinically, the level of CCL7 in blood was positively related to the number of Mo-MDSCs in CCR patients, and highly linked with the short-time recurrence and distant metastasis. CCL7 secreted by Mo-MDSCs plays an important role in initiating the outgrowth of metastatic latent CRC cells. Inhibition of CCL7 might provide a potential therapeutic strategy for the prevention of metastasis recurrence.

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Malignant subclone drives metastasis of genetically and phenotypically heterogenous cell clusters through fibrotic niche generation

Nature Communications ◽

10.1038/s41467-021-21160-0 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Sau Yee Kok ◽

Hiroko Oshima ◽

Kei Takahashi ◽

Mizuho Nakayama ◽

Kazuhiro Murakami ◽

...

Keyword(s):

Tumor Cell ◽

Primary Site ◽

Cell Depletion ◽

Driver Mutations ◽

Effective Strategy ◽

Malignant Cells ◽

Early Step ◽

Cell Clusters ◽

Metastatic Cells

AbstractA concept of polyclonal metastasis has recently been proposed, wherein tumor cell clusters break off from the primary site and are disseminated. However, the involvement of driver mutations in such polyclonal mechanism is not fully understood. Here, we show that non-metastatic AP cells metastasize to the liver with metastatic AKTP cells after co-transplantation to the spleen. Furthermore, AKTP cell depletion after the development of metastases results in the continuous proliferation of the remaining AP cells, indicating a role of AKTP cells in the early step of polyclonal metastasis. Importantly, AKTP cells, but not AP cells, induce fibrotic niche generation when arrested in the sinusoid, and such fibrotic microenvironment promotes the colonization of AP cells. These results indicate that non-metastatic cells can metastasize via the polyclonal metastasis mechanism using the fibrotic niche induced by malignant cells. Thus, targeting the fibrotic niche is an effective strategy for halting polyclonal metastasis.

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Adhesion strength and contractility enable metastatic cells to become adurotactic

Cell Reports ◽

10.1016/j.celrep.2021.108816 ◽

2021 ◽

Vol 34 (10) ◽

pp. 108816

Author(s):

Benjamin Yeoman ◽

Gabriel Shatkin ◽

Pranjali Beri ◽

Afsheen Banisadr ◽

Parag Katira ◽

...

Keyword(s):

Adhesion Strength ◽

Metastatic Cells

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Targeting the Metabolic Adaptation of Metastatic Cancer

Cancers ◽

10.3390/cancers13071641 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1641

Author(s):

Josep Tarragó-Celada ◽

Marta Cascante

Keyword(s):

Colorectal Cancer ◽

Cancer Metastasis ◽

Metastatic Cancer ◽

Breast Cancer Metastasis ◽

Metabolic Inhibitors ◽

Current Status ◽

Metabolic Adaptation ◽

Metastatic Cells ◽

Colorectal Cancer Metastasis ◽

Metastatic Process

Metabolic adaptation is emerging as an important hallmark of cancer and metastasis. In the last decade, increasing evidence has shown the importance of metabolic alterations underlying the metastatic process, especially in breast cancer metastasis but also in colorectal cancer metastasis. Being the main cause of cancer-related deaths, it is of great importance to developing new therapeutic strategies that specifically target metastatic cells. In this regard, targeting metabolic pathways of metastatic cells is one of the more promising windows for new therapies of metastatic colorectal cancer, where still there are no approved inhibitors against metabolic targets. In this study, we review the recent advances in the field of metabolic adaptation of cancer metastasis, focusing our attention on colorectal cancer. In addition, we also review the current status of metabolic inhibitors for cancer treatment.

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BSCI-20. THERAPEUTIC TARGETING OF HLA-G IN BRAIN METASTASES

Neuro-Oncology Advances ◽

10.1093/noajnl/vdz014.018 ◽

2019 ◽

Vol 1 (Supplement_1) ◽

pp. i5-i5

Author(s):

Sheila Singh ◽

Blessing Bassey-Archibong ◽

Nikoo Aghaei ◽

Agata Kieliszek ◽

Chitra Venugopal ◽

...

Keyword(s):

Brain Metastases ◽

Systemic Disease ◽

Human Leukocyte ◽

Genetic Profile ◽

Whole Brain Radiation ◽

Metastatic Cells ◽

Metastatic Process ◽

Xenograft Models ◽

Sphere Formation ◽

The Brain

Abstract Brain metastases (BM) are the most common brain tumor in adults, with an incidence ten times greater than that of primary brain tumors. The most common sources of BM in adult cancer patients include cancers of the lung, breast and melanoma, which together account for almost 80% of all BM. Current clinical modalities for BM include surgery, whole brain radiation therapy and stereotactic radiosurgery but these therapies still offer limited efficacy and reduced survival of only months in treated patients, emphasizing the need for novel BM research approaches and better therapeutic strategies. Our laboratory recently discovered that stem-like cells exist in patient-derived BM from lung, breast and melanoma cancers, which we termed “brain metastasis-initiating cells” or BMICs. Through clinically relevant human-mouse xenograft models established with these patient-derived BMICs, we captured lung, breast and melanoma BMICs at pre-metastasis – a key stage where circulating metastatic cells extravasate and initially seed the brain, prior to organization into micro-metastatic foci. Transcriptome analysis of pre-metastatic BMICs revealed a unique genetic profile and several genes commonly up-regulated among lung, breast and melanoma BM, including the non-classical human leukocyte class I antigen-G (HLA-G). Loss of HLA-G in lung, breast and melanoma BMICs using two HLA-G specific shRNAs attenuated sphere formation, migratory and tumor initiating abilities of lung, breast and melanoma BMICs compared to control BMICs. HLA-G knockdown also resulted in reduced phospho(p)-STAT3 expression in patient-derived BMICs suggesting a potential cooperative role between HLA-G and pSTAT3 in BM. Since HLA-G is highly expressed at the cell surface in control tumors, ongoing experiments are focused on developing HLA-G specific chimeric antigen receptor -T cells (CAR-Ts) and determining their efficacy in targeting lung-, breast- and melanoma-BM as blocking the brain metastatic process will markedly extend patient survival and ultimately transform a fatal systemic disease into a more treatable one.

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Metastasis suppressor genes: signal transduction, cross-talk and the potential for modulating the behavior of metastatic cells

Anti-Cancer Drugs ◽

10.1097/01.cad.0000132233.36512.fa ◽

2004 ◽

Vol 15 (6) ◽

pp. 559-568 ◽

Cited By ~ 9

Author(s):

Jonathan C. Berger ◽

Donald Vander Griend ◽

Walter M. Stadler ◽

Carrie Rinker-Schaeffer

Keyword(s):

Signal Transduction ◽

Cross Talk ◽

Metastasis Suppressor ◽

Suppressor Genes ◽

Metastasis Suppressor Genes ◽

Metastatic Cells

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