Cancer Cells Promote Phenotypic Alterations in Hepatocytes at the Edge of Cancer Cell Nests to Facilitate Vessel Co-Option Establishment in Colorectal Cancer Liver Metastases

Rada, Miran; Tsamchoe, Migmar; Kapelanski-Lamoureux, Audrey; Hassan, Nour; Bloom, Jessica L.; Petrillo, Stephanie; Kim, Diane H.; Lazaris, Anthoula; Metrakos, Peter

doi:10.3390/cancers14051318

Cited by 13 publications

(21 citation statements)

References 69 publications

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“…Therefore, cells in close proximity to VCO lesions must undergo phenotypic alterations so that the displacement by cancer cells could occur. In a VCO-dependent CRCLM model, apoptosis, motility and EMT were induced in tumor-adjacent hepatocytes by the cancer cells via upregulation of proapoptotic cleaved caspase-3 and cleaved PARP-1, EMT-related vimentin and motility-mediated ARP2/3 ( 113 ). This resulted in hepatocyte displacement and formation of vessel co-opted metastases.…”

Section: Potential Therapeutic Anti-tumor Vessel Co-option Strategiesmentioning

confidence: 99%

Tumor vessel co-option: The past & the future

et al. 2022

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Tumor vessel co-option (VCO) is a non-angiogenic vascularization mechanism that is a possible cause of resistance to anti-angiogenic therapy (AAT). Multiple tumors are hypothesized to primarily rely on growth factor signaling-induced sprouting angiogenesis, which is often inhibited during AAT. During VCO however, tumors invade healthy tissues by hijacking pre-existing blood vessels of the host organ to secure their blood and nutrient supply. Although VCO has been described in the context of AAT resistance, the molecular mechanisms underlying this process and the profile and characteristics of co-opted vascular cell types (endothelial cells (ECs) and pericytes) remain poorly understood, resulting in the lack of therapeutic strategies to inhibit VCO (and to overcome AAT resistance). In the past few years, novel next-generation technologies (such as single-cell RNA sequencing) have emerged and revolutionized the way of analyzing and understanding cancer biology. While most studies utilizing single-cell RNA sequencing with focus on cancer vascularization have centered around ECs during sprouting angiogenesis, we propose that this and other novel technologies can be used in future investigations to shed light on tumor EC biology during VCO. In this review, we summarize the molecular mechanisms driving VCO known to date and introduce the models used to study this phenomenon to date. We highlight VCO studies that recently emerged using sequencing approaches and propose how these and other novel state-of-the-art methods can be used in the future to further explore ECs and other cell types in the VCO process and to identify potential vulnerabilities in tumors relying on VCO. A better understanding of VCO by using novel approaches could provide new answers to the many open questions, and thus pave the way to develop new strategies to control and target tumor vascularization.

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Section: Potential Therapeutic Anti-tumor Vessel Co-option Strategiesmentioning

confidence: 99%

Tumor vessel co-option: The past & the future

et al. 2022

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“…Our previous publications suggested higher levels of TGFβ1 in the conditioned media of cocultured IHH hepatocytes with colorectal cancer cells in comparison to the conditioned media of the same cells individually, which is incited by higher expression levels of TGFβ1 in the cocultured hepatocytes and cancer cells 17,21 . Therefore, we questioned whether co-culturing IHH hepatocytes with cancer cells induce the expression of Ang1 through TGFβ1.…”

Section: Cancer Cells Promote Ang1 Expression In Hepatocytesmentioning

confidence: 93%

Disruption of integrin alpha-5/beta-1-dependent transforming growth factor beta-1 signaling pathway attenuates vessel co-option in colorectal cancer liver metastases

Rada

Kapelanski-Lamoureux

Zlotnik

et al. 2022

Preprint

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Colorectal cancer liver metastases (CRCLM) have two major histopathological growth patterns (HGPs) including angiogenic desmoplastic HGP (DHGP) and non-angiogenic replacement HGP (RHGP). The RHGP lesions obtain their blood supply through vessel co-option, where the cancer cells hijack the pre-existing blood vessels of the surrounding liver tissue. Consequently, anti-angiogenic therapies are less efficacious in CRCLM patients with RHGP lesions. Recently, we identified a positive correlation between the expression of Angiopoietin1 (Ang1) and the development of vessel co-opted CRCLM lesions in vivo. However, the mechanisms underlying Ang1 upregulation in vessel co-opting CRCLM lesions are unclear. Herein, we demonstrated that transforming growth factor β1 (TGFβ1) modulates the expression of Ang1 in hepatocytes in vitro. Significantly, pharmaceutical inhibition of integrin alpha-5/beta-1 (ITGα5β1) through ATN-161 impaired TGFβ1-dependent Ang1 expression in vitro and in vivo. Moreover, blocking ITGα5β1 attenuated the formation of vessel co-opting lesions. Furthermore, treatment with ATN-161 significantly improved survival in tumour-bearing mice. Taken together, our results suggest the molecular mechanism of Ang1 upregulation in vessel co-opting CRCLM and targeting this pathway may serve as promising therapeutic strategy to overcome the development of vessel co-option in CRCLM.

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“…We performed co-immunostaining for FFPE sections as described in previous publications [10,24]. Briefly, we performed deparaffinization, hydration, antigen retrieval and blocking of endogenous peroxidase activity and non-specific binding as described in the immunohistochemical staining section above.…”

Section: Immunofluorescence Stainingmentioning

confidence: 99%

“…We performed the scratch assay as described in Rada et al [24] and Ibrahim et al [17]. Briefly, the cells (0.5 × 10 6 ) were cultured in 6-well plates and incubated at 37 • C with 5% CO 2 .…”

Section: Scratch Assaymentioning

confidence: 99%

“…Indeed, the expression levels of ARP2/3 in the metastatic cancer cells were significantly correlated with the presence of Ang1 in the liver tissue (Figure 2b). To determine whether ARP2/3 mediates Ang1-driven cancer motility, we knocked down ARPC3, a subunit of ARP2/3, using ARPC3-specific shRNA in SW620 and COLO320DM cancer cells (Figure 3a,b), followed by scratch assay [17,[24][25][26] (Figure 3c,d). The data showed significant elevation in the migratory capacity of cancer cells upon Ang1 exposure, whilst the effect of Ang1 on cancer cell motility was abolished in the cancer cells To determine whether ARP2/3 mediates Ang1-driven cancer motility, we knocked down ARPC3, a subunit of ARP2/3, using ARPC3-specific shRNA in SW620 and COLO320DM cancer cells (Figure 3a,b), followed by scratch assay [17,[24][25][26] (Figure 3c,d).…”

Section: Ang1 Induces Cancer Cell Motility Through Arp2/3mentioning

confidence: 99%

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Angiopoietin-1 Upregulates Cancer Cell Motility in Colorectal Cancer Liver Metastases through Actin-Related Protein 2/3

Rada

Kapelanski-Lamoureux

Tsamchoe

et al. 2022

Cancers

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Resistance to anti-angiogenic therapy is a major challenge in the treatment of colorectal cancer liver metastases (CRCLMs). Vessel co-option has been identified as a key contributor to anti-angiogenic therapy resistance in CRCLMs. Recently, we identified a positive correlation between the expression of Angiopoietin1 (Ang1) in the liver and the development of vessel co-opting CRCLM lesions in vivo. However, the mechanisms underlying its stimulation of vessel co-option are unclear. Herein, we demonstrated Ang1 as a positive regulator of actin-related protein 2/3 (ARP2/3) expression in cancer cells, in vitro and in vivo, which is known to be essential for the formation of vessel co-option in CRCLM. Significantly, Ang1-dependent ARP2/3 expression was impaired in the cancer cells upon Tie2 or PI3K/AKT inhibition in vitro. Taken together, our results suggest novel mechanisms by which Ang1 confers the development of vessel co-option in CRCLM, which, targeting this pathway, may serve as promising therapeutic targets to overcome the development of vessel co-option in CRCLM.

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Cancer Cells Promote Phenotypic Alterations in Hepatocytes at the Edge of Cancer Cell Nests to Facilitate Vessel Co-Option Establishment in Colorectal Cancer Liver Metastases

Cited by 13 publications

References 69 publications

Tumor vessel co-option: The past & the future

Tumor vessel co-option: The past & the future

Disruption of integrin alpha-5/beta-1-dependent transforming growth factor beta-1 signaling pathway attenuates vessel co-option in colorectal cancer liver metastases

Angiopoietin-1 Upregulates Cancer Cell Motility in Colorectal Cancer Liver Metastases through Actin-Related Protein 2/3

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