Liver Metastasis Is Facilitated by the Adherence of Circulating Tumor Cells to Vascular Fibronectin Deposits

Barbazán, Jorge; Alonso-Alconada, Lorena; Elkhatib, Nadia; Geraldo, Sara; Gurchenkov, Vasily; Glentis, Alexandros; Niel, Guillaume van; Palmulli, Roberta; Fernández, B. Díaz; Viaño, Patricia; García‐Caballero, Tomás; López‐López, Rafael; Abal, Miguel; Vignjević, Danijela

doi:10.1158/0008-5472.can-16-1917

Cited by 66 publications

(47 citation statements)

References 40 publications

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“…Fibronectin adhere to CTC membrane integrins through endothelial gaps produced by reactive oxygen species (ROS) in the tumor microenvironment and aid in the arrest of CTC in the PMN vasculature (Fig. ) …”

Section: Preparing New Settlements—the Premetastatic Nichesmentioning

confidence: 99%

Premetastatic niches, exosomes and circulating tumor cells: Early mechanisms of tumor dissemination and the relation to surgery

Raskov

Orhan

Salanti

et al. 2020

Intl Journal of Cancer

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The physiological stress response to surgery promotes wound healing and functional recovery and includes the activation of neural, inflammatory and proangiogenic signaling pathways. Paradoxically, the same pathways also promote metastatic spread and growth of residual cancer. Human and animal studies show that cancer surgery can increase survival, migration and proliferation of residual tumor cells. To secure the survival and growth of disseminated tumor cells, the formation of premetastatic niches in target organs involves a complex interplay between microenvironment, immune system, circulating tumor cells, as well as chemical mediators and exosomes secreted by the primary tumor. This review describes the current understanding of the early mechanisms of dissemination, as well as how surgery may facilitate disease progression.

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Section: Preparing New Settlements—the Premetastatic Nichesmentioning

confidence: 99%

Premetastatic niches, exosomes and circulating tumor cells: Early mechanisms of tumor dissemination and the relation to surgery

Raskov

Orhan

Salanti

et al. 2020

Intl Journal of Cancer

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“…S7). As alterations of the extracellular matrix could promote metastasis (15), its composition was also analyzed. Although periendothelial deposition of collagen 1, collagen 3, collagen 4, and fibronectin was not altered, Lama4 was strongly increased in the subendothelial space of Disse ( Fig.…”

Section: Hepatic Endothelial Notch Activation Causes Sinusoidal Capilmentioning

confidence: 99%

“…More recently, endothelial lectins such as Clec4g were shown to mediate colorectal cancer metastasis to the liver (14). In addition, hepatic endothelial fibronectin deposits have been shown to bind circulating tumor cells via talin1, a component of focal adhesions (15). The importance of LSEC in the control of liver metastasis is also underlined by the long-known fact that cirrhotic livers harbor less metastases than non-cirrhotic livers (16).…”

Section: Introductionmentioning

confidence: 99%

Hepatic Endothelial Notch Activation Protects against Liver Metastasis by Regulating Endothelial-Tumor Cell Adhesion Independent of Angiocrine Signaling

et al. 2019

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The interaction of tumor cells with organ-specific endothelial cells (EC) is an important step during metastatic progression. Notch signaling in organ-specific niches has been implicated in mediating opposing effects on organotropic metastasis to the lungs and the liver, respectively. In this study, we scrutinized the role of endothelial Notch activation during liver metastasis. To target hepatic EC (HEC), a novel EC subtype-specific Cre driver mouse was generated. Clec4g-Cre tg/wt mice were crossed to Rosa26 N1ICD-IRES-GFP to enhance Notch signaling in HEC (NICD OE-HEC). In NICD OE-HEC mice, hepatic metastasis of malignant melanoma and colorectal carcinoma was significantly reduced. These mice revealed reduced liver growth and impaired metabolic zonation due to suppression of hepatic angiocrine Wnt signaling. Hepatic metastasis, however, was not controlled by angiocrine Wnt signaling, as deficiency of the Wnt cargo receptor Wls in HEC of Wls HEC-KO mice did not affect hepatic metastasis. In contrast, the hepatic microvasculature in NICD OE-HEC mice revealed a special form of sinusoidal capillarization, with effacement of endothelial zonation functionally paralleled by reduced tumor cell adhesion in vivo. Notably, expression of endothelial adhesion molecule ICAM1 by HEC was significantly reduced. Treatment with an anti-ICAM1 antibody significantly inhibited tumor cell adhesion to HEC in wild-type mice confirming that Notch controls hepatic metastasis via modulation of HEC adhesion molecules. As endothelial Notch activation in the lung has been shown to promote lung metastasis, tumor therapy will require approaches that target Notch in an organ-, cell type-, and context-specific manner. Significance: Manipulation of Notch signaling in the endothelium has opposing, organ-specific effects on metastasis to the lung and the liver, demonstrating that this pathway should be targeted in a cell-and context-specific fashion.

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“…These markers included TIMP1 and CLU , selected in a previous global gene expression profiling study developed in our group [16], VIL1 as an epithelial marker, and LOXL3 and ZEB2 as transcription factors involved in EMT and associated with metastasis dissemination. We also included TLN1 as a gene involved in CTCs extravasation during metastatic dissemination [17]. GAPDH was also included as a marker of global cellularity.…”

Section: Resultsmentioning

confidence: 99%

Predicting Outcome and Therapy Response in mCRC Patients Using an Indirect Method for CTCs Detection by a Multigene Expression Panel: A Multicentric Prospective Validation Study

Insua

Cámara

Vázquez

et al. 2017

IJMS

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Colorectal cancer (CRC) is one of the major causes of cancer-related deaths. Early detection of tumor relapse is crucial for determining the most appropriate therapeutic management. In clinical practice, computed tomography (CT) is routinely used, but small tumor changes are difficult to visualize, and reliable blood-based prognostic and monitoring biomarkers are urgently needed. The aim of this study was to prospectively validate a gene expression panel (composed of GAPDH, VIL1, CLU, TIMP1, TLN1, LOXL3 and ZEB2) for detecting circulating tumor cells (CTCs) as prognostic and predictive tool in blood samples from 94 metastatic CRC (mCRC) patients. Patients with higher gene panel expression before treatment had a reduced progression-free survival (PFS) and overall-survival (OS) rates compared with patients with low expression (p = 0.003 and p ≤ 0.001, respectively). Patients with increased expression of CTCs markers during treatment presented PFS and OS times of 8.95 and 11.74 months, respectively, compared with 14.41 and 24.7 for patients presenting decreased expression (PFS; p = 0.020; OS; p ≤ 0.001). Patients classified as non-responders by CTCs with treatment, but classified as responders by CT scan, showed significantly shorter survival times (PFS: 8.53 vs. 11.70; OS: 10.37 vs. 24.13; months). In conclusion, our CTCs detection panel demonstrated efficacy for early treatment response assessment in mCRC patients, and with increased reliability compared to CT scan.

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Liver Metastasis Is Facilitated by the Adherence of Circulating Tumor Cells to Vascular Fibronectin Deposits

Cited by 66 publications

References 40 publications

Premetastatic niches, exosomes and circulating tumor cells: Early mechanisms of tumor dissemination and the relation to surgery

Premetastatic niches, exosomes and circulating tumor cells: Early mechanisms of tumor dissemination and the relation to surgery

Hepatic Endothelial Notch Activation Protects against Liver Metastasis by Regulating Endothelial-Tumor Cell Adhesion Independent of Angiocrine Signaling

Predicting Outcome and Therapy Response in mCRC Patients Using an Indirect Method for CTCs Detection by a Multigene Expression Panel: A Multicentric Prospective Validation Study

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