Origin and Distribution of Connective Tissue and Pericytes Impacting Vascularization in Brain Metastases With Different Growth Patterns

Téglási, Vanda; Csűry, Tamás Dániel; Dezső, Katalin; Bugyik, Edina; Szabó, V.; Szállási, Zoltán; Paku, Sándor; Reiniger, Lilla

doi:10.1093/jnen/nlz007

Cited by 24 publications

(26 citation statements)

References 38 publications

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“…Embedded in the inner, endothelial layer of the vascular basal lamina, pericytes substantially contribute to the secretion of matrix proteins [35], which might be particularly important in metastatic tumors, which tend to detach astrocytesanother major source of basal membrane proteinsfrom co-opted vessels. This is in line with accumulation of collagen secreted by perivascular cells observed in papillary-type human brain metastases [21].…”

Section: Discussionsupporting

confidence: 78%

“…In human TNBC brain metastases, PDGFRb-positive perivascular cells were found in the stroma (Fig. 1B), in single or multiple layers, as previously shown [21]. In addition, we have also detected single pericyte-like cells expressing the specific markers PDGFRb and CD13, scattered among the tumor cells, especially in less cell-dense areas, probably in the proximity of necrotic zones (Fig.…”

Section: Direct Interaction Of Brain Metastatic Tumor Cells With Perisupporting

confidence: 85%

“…Implicated in extravasation of malignant cells through the BBB and influencing their ability to survive and proliferate in the cerebral environment, cells of the NVU have been increasingly recognized as key players in brain metastasis formation. Although interactions between metastatic cells and CECs, astrocytes, or microglia are relatively well characterized [6], our knowledge about the role of pericytes is restricted to indirect effects on tumor cells, including regulation of blood-tumor barrier permeability [28] and secretion of connective tissue proteins [21]. By remodeling the perivascular niche [29], increasing angiogenesis [29], and acquiring an immunosuppressive function [31,32], pericytes have undisputed roles in promoting primary brain tumors.…”

Section: Discussionmentioning

confidence: 99%

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Pericyte‐secreted IGF2 promotes breast cancer brain metastasis formation

et al. 2020

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Brain metastases are life‐threatening complications of triple‐negative breast cancer, melanoma, and a few other tumor types. Poor outcome of cerebral secondary tumors largely depends on the microenvironment formed by cells of the neurovascular unit, among which pericytes are the least characterized. By using in vivo and in vitro techniques and human samples, here we show that pericytes play crucial role in the development of metastatic brain tumors by directly influencing key steps of the development of the disease. Brain pericytes had a prompt chemoattractant effect on breast cancer cells and established direct contacts with them. By secreting high amounts of extracellular matrix proteins, pericytes enhanced adhesion of both melanoma and triple‐negative cancer cells, which might be particularly important in the exclusive perivascular growth of these tumor cells. In addition, pericytes secreted insulin‐like growth factor 2 (IGF2), which had a very significant pro‐proliferative effect on mammary carcinoma, but not on melanoma cells. By inhibiting IGF2 signaling using silencing or picropodophyllin (PPP), we could block the proliferation‐increasing effect of pericytes on breast cancer cells. Administration of PPP (a blood–brain barrier‐permeable substance) significantly decreased the size of brain tumors in mice inoculated with triple‐negative breast cancer cells. Taken together, our results indicate that brain pericytes have significant pro‐metastatic features, especially in breast cancer. Our study underlines the importance of targeting pericytes and the IGF axis as potential strategies in brain metastatic diseases.

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Section: Discussionsupporting

confidence: 78%

Section: Direct Interaction Of Brain Metastatic Tumor Cells With Perisupporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

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Pericyte‐secreted IGF2 promotes breast cancer brain metastasis formation

et al. 2020

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“…Both CECs and astrocytes have a Janus-faced attitude, bearing both tumour-destructive and -protective mechanisms [40]. Much less is known about the role of pericytes, which regulate the permeability of the blood-tumour barrier [20] and contribute to connective tissue accumulation in the metastases [33].…”

Section: Discussionmentioning

confidence: 99%

Response of the neurovascular unit to brain metastatic breast cancer cells

Haskó

Fazakas

Molnár

et al. 2019

acta neuropathol commun

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Therapeutic resistance of cerebral secondary tumours largely depends on unique aspects linked to the neurovascular unit, especially cerebral endothelial cells and astrocytes. By using advanced microscopy techniques, here we explored novel mechanisms related to the neurovascular unit during extravasation and proliferation of triple negative breast cancer cells in the brain. Metastatic mammary carcinoma cells arrested and elongated within one hour in cerebral microvessels, but their number decreased by almost 80% in the first two days. Interestingly, malignant cells induced vasoconstriction and development of intraluminal endothelial plugs, which isolated invading cells from the circulation. During diapedesis – which usually took place on day four and five after inoculation of the tumour cells – continuity of cerebral endothelial tight junctions remained intact, indicating migration of cancer cells through the transcellular pathway. In addition, metastatic cells induced formation of multiluminal vessels and claudin-5-positive endothelial blebs. However, even severe endothelial blebbing could be reversed and the vessel morphology was restored shortly after the tumour cells completed transendothelial migration. Similar to neuro-inflammatory leukocytes, tumour cells migrated not only through the endothelial layer, but through the glia limitans perivascularis as well. Nevertheless, along with the growth of metastatic lesions by co-option of pre-existing capillaries, astrocytes and astrocyte end-feet were gradually expelled from the vessels to the border of the tumour. Taken together, we identified previously unknown mechanisms involved in the reaction of brain resident cells to invading breast cancer cells. Our results contribute to a better understanding of the complex cross-talk between tumour cells and host cells in the brain, which is essential for the identification of new therapeutic targets in this devastating disease. Electronic supplementary material The online version of this article (10.1186/s40478-019-0788-1) contains supplementary material, which is available to authorized users.

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“…Brain‐specific metastasis and the brain microenvironment. Brain metastasizing cells interact with brain microenvironmental cells such as endothelial cells, 80,129,130,217,218,231,232 astrocytes 238,243 and microglia 250,253,255 and with other components of the brain microenvironment (eg, ECM). These interactions may either inhibit or promote brain metastasis…”

Section: Brain Metastasizing Tumor Cells Colonize a Unique Microenvirmentioning

confidence: 99%

Site‐specific metastasis: A cooperation between cancer cells and the metastatic microenvironment

Izraely

2020

Intl Journal of Cancer

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The conclusion derived from the information provided in this review is that disseminating tumor cells (DTC) collaborate with the microenvironment of a future metastatic organ site in the establishment of organ‐specific metastasis. We review the basic principles of site‐specific metastasis and the contribution of the cross talk between DTC and the microenvironment of metastatic sites (metastatic microenvironment [MME]) to the establishment of the organ‐specific premetastatic niche; the targeted migration of DTC to the endothelium of the future organ‐specific metastasis; the transmigration of DTC to this site and the seeding and colonization of DTC in their future MME. We also discuss the role played by DTC‐MME interactions on tumor dormancy and on the differential response of tumor cells residing in different MMEs to antitumor therapy. Finally, we summarize some studies dealing with the effects of the MME on a unique site‐specific metastasis—brain metastasis.

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Origin and Distribution of Connective Tissue and Pericytes Impacting Vascularization in Brain Metastases With Different Growth Patterns

Cited by 24 publications

References 38 publications

Pericyte‐secreted IGF2 promotes breast cancer brain metastasis formation

Pericyte‐secreted IGF2 promotes breast cancer brain metastasis formation

Response of the neurovascular unit to brain metastatic breast cancer cells

Site‐specific metastasis: A cooperation between cancer cells and the metastatic microenvironment

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