Loss of Tumorigenicity and Metastatic Potential in Carcinoma Cells Expressing the Extracellular Domain of the Type 1 Insulin-Like Growth Factor Receptor

Samani, Amir; Chevet, Éric; Fallavollita, Lucia; Galipeau, Jacques; Brodt, Pnina

doi:10.1158/0008-5472.can-03-3780

Cited by 54 publications

(46 citation statements)

References 22 publications

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“…Previously, we identified the IGF-IR as a key regulator of the liver-metastasizing phenotype in a Lewis lung carcinoma-based model of organ site-specific metastasis (Brodt et al, 2001;Samani et al, 2004). The present study was prompted by our finding, based on gene chip microarray analysis, that in this model, the acquisition of a liver-metastasizing phenotype was associated with markedly increased type IV collagen a1 and a2 expression levels.…”

Section: Introductionmentioning

confidence: 81%

“…Some of these factors have also been shown to play important roles during the early stages of liver metastasis (VidalVanaclocha, 2008). The documented role of HIF-1a in the regulation of collagen IV synthesis is also of relevance to our animal model because IGF-I is a known inducer of HIF-1a synthesis via mitogenactivated protein kinase and phosphatidylinositol 3-kinase signaling (Samani et al, 2007), and we have previously documented that several HIF-1a-dependent genes such as VEGF-A (vascular endothelial growth factor A) and VEGF-C (vascular endothelial growth factor C) are upregulated in M-2-7 IGFÀIR cells (Tang et al, 2003;Samani et al, 2004). The possible role of HIF-1a in collagen IV upregulation seen in our cells remains to be further explored.…”

Section: Lung Metastasismentioning

confidence: 98%

“…Subcutaneous tumors were generated by the injection of 2 Â 10 5 cells subcutaneous into mice and tumor volumes calculated as described (Samani et al, 2004). Experimental liver metastases were generated by intrasplenic/portal injections of 1 Â 10 5 M-27 IGFÀIR or 5 Â 10 4 MC-38 cells, followed by splenectomy, as previously described (Long et al, 1995;Brodt et al, 2001).…”

Section: Immunoprecipitationmentioning

confidence: 99%

“…Apoptotic cells were detected using a TUNEL assay as described (Samani et al, 2004). To visualize nuclei and detect mitotic spindles, 4,6-diamidino-2-phenylindole staining was used.…”

Section: Anoikis Assaymentioning

confidence: 99%

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Type IV collagen-initiated signals provide survival and growth cues required for liver metastasis

et al. 2011

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The liver is a major site of metastasis for human malignancies, yet the factors that regulate tumor cell survival and growth in this organ remain elusive. Previously, we reported that M-27 IGFÀIR murine lung carcinoma cells with ectopic insulin-like growth factor-1 (IGF-I) receptor overexpression acquired a site-specific, liver-metastasizing potential. Gene expression profiling and subsequent RNA and protein analyses revealed that this was associated with major changes to the expression of extracellular matrix (ECM) protein-encoding genes including type III, IV and XVIII collagen genes, and these changes were also observed in the respective tumors in vivo. Because type IV collagen was the most prominently altered ECM protein in this model, we further analyzed its functional relevance to liver metastasis. M-27 cells stably overexpressing type IV collagen a1 and a2 chains were generated and their growth and metastatic properties investigated. We found that these cells acquired a site-selective growth advantage in the liver and this was associated with cell rescue from anoikis in a collagen IV/a2 integrin/FAK-dependent manner and increased responsiveness to IGF-I. Conversely, collagen IV or focal adhesion kinase (FAK) silencing by smallinterfering RNA in highly metastatic tumor cells enhanced anoikis and decreased liver metastases formation. Moreover, analysis of human surgical specimens revealed uniformly high collagen IV expression in 65/65 hepatic metastases analyzed, regardless of tissue of origin, whereas it was variable and generally low in 50/50 primary colorectal carcinoma specimens examined. The results suggest that collagen IV-conveyed signals are essential cues for liver metastasis in diverse tumor types and identify mediators of collagen IV signaling as potential therapeutic targets in the management of hepatic metastases.

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Section: Introductionmentioning

confidence: 81%

Section: Lung Metastasismentioning

confidence: 98%

Section: Immunoprecipitationmentioning

confidence: 99%

“…Apoptotic cells were detected using a TUNEL assay as described (Samani et al, 2004). To visualize nuclei and detect mitotic spindles, 4,6-diamidino-2-phenylindole staining was used.…”

Section: Anoikis Assaymentioning

confidence: 99%

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Type IV collagen-initiated signals provide survival and growth cues required for liver metastasis

et al. 2011

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“…They were performed essentially as we described previously, using 10 ng/ ml rhIGF-I (USBiological, Swampscott, MA, USA) or Des (1-3)-IGF-I (GroPep, Thebarton, SA, Australia) and 200 ng/ ml IGF-II (Sigma Chemicals, St Louis, MO, USA) for stimulation (Samani et al, 2004). To measure anchorageindependent growth, a modification of the standard soft agar cloning assay was used, as we described previously .…”

Section: Functional In Vitro Assaysmentioning

confidence: 99%

Loss of responsiveness to IGF-I in cells with reduced cathepsin L expression levels

et al. 2008

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The lysosomal cysteine proteinase cathepsin L is involved in proteolytic processing of internalized proteins. In transformed cells, where it is frequently overexpressed, its intracellular localization and functions can be altered. Previously, we reported that treatment of highly metastatic, murine carcinoma H-59 cells with small molecule cysteine proteinase inhibitors altered the responsiveness of the type I insulin-like growth factor (IGF-I) receptor and consequently reduced cell invasion and metastasis. To assess more specifically the role of cathepsin L in IGF-I-induced signaling and tumorigenicity, we generated H-59 subclones with reduced cathepsin L expression levels. These clonal lines showed an altered responsiveness to IGF-I in vitro, as evidenced by (i) loss of IGF-I-induced receptor phosphorylation and Shc recruitment, (ii) reduced IGF-I (but not IGF-II)-induced cellular proliferation and migration, (iii) decreased anchorage-independent growth and (iv) reduced plasma membrane levels of IGF-IR. These changes resulted in increased apoptosis in vivo and an impaired ability of the cells to form liver metastases. The results demonstrate that cathepsin L expression levels regulate cell responsiveness to IGF-I and thereby identify a novel function for cathepsin L in the control of the tumorigenic/metastatic phenotype.

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Vascularization of colorectal carcinoma liver metastasis: insight into stratification of patients for anti‐angiogenic therapies

Lazaris

Achour

Petrillo

et al. 2018

The Journal of Pathology CR

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Current treatment for metastatic disease targets angiogenesis. With the increasing data demonstrating that cancer cells do not entirely rely on angiogenesis but hijack the existing vasculature through mechanisms such as co‐option of existing blood vessels, identification of targets has become of utmost importance. Our study looks at the vasculature of chemonaïve and treated colorectal carcinoma liver metastases (CRCLMs) to obtain a basic understanding of the microvessel density, type of vasculature (mature versus immature), and correlation with histopathological growth patterns that demonstrate unique patterns of angiogenesis. We performed immunohistochemistry on chemonaïve sections of desmoplastic histopathological growth pattern (DHGP) and replacement histopathological growth patterns (RHGP) lesions with CD31 [endothelial cell (EC) marker] and CD34/Ki67 double staining, which denotes proliferating ECs. The CD31 stains demonstrated a lower microvascular CD31 +ve capillary density in the DHGP versus RHGP lesions; and integrating both immunostains with CD34/Ki67 staining on serial sections revealed proliferating vessels in DHGP lesions and co‐option of mature existing blood vessels in RHGP lesions. Interestingly, upon treatment with chemotherapy and bevacizumab, the RHGP lesions showed no necrosis whereas the DHGP lesions had almost 100% necrosis of the cancer cells and in most cases there was a single layer of viable cancer cells, just under or within the desmoplastic ring. The survival of these cells may be directly related to spatial location and possibly a different microenvironment, which may involve adhesion to different extracellular matrix components and/or different oxygen/nutrient availability. This remains to be elucidated. We provide evidence that DHGP CRCLMs obtain their blood supply via sprouting angiogenesis whereas RHGP lesions obtain their blood supply via co‐option of existing vasculature. Furthermore current treatment regimens do not affect RHGP lesions and although they kill the majority of the cancer cells in DHGP lesions, there are cells surviving within or adjacent to the desmoplastic ring which could potentially give rise to a growing lesion.

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Loss of Tumorigenicity and Metastatic Potential in Carcinoma Cells Expressing the Extracellular Domain of the Type 1 Insulin-Like Growth Factor Receptor

Cited by 54 publications

References 22 publications

Type IV collagen-initiated signals provide survival and growth cues required for liver metastasis

Type IV collagen-initiated signals provide survival and growth cues required for liver metastasis

Loss of responsiveness to IGF-I in cells with reduced cathepsin L expression levels

Vascularization of colorectal carcinoma liver metastasis: insight into stratification of patients for anti‐angiogenic therapies

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