Article (Scientific journals)
Metastatic colorectal cancer cells maintain the TGFβ program and use TGFBI to fuel angiogenesis.
Chiavarina, Barbara; Costanza, Brunella; Ronca, Roberto et al.
2021In Theranostics, 11 (4), p. 1626-1640
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Keywords :
alternative TGFβ signaling; endothelial cells; liver metastases
Abstract :
[en] Colorectal cancer (CRC) cells are traditionally considered unresponsive to TGFβ due to mutations in the receptors and/or downstream signaling molecules. TGFβ influences CRC cells only indirectly via stromal cells, such as cancer-associated fibroblasts. However, CRC cell ability to directly respond to TGFβ currently remains unexplored. This represents a missed opportunity for diagnostic and therapeutic interventions. Methods: We examined whether cancer cells from primary CRC and liver metastases respond to TGFβ by inducing TGFβ-induced protein ig-h3 (TGFBI) expression, and the contribution of canonical and non-canonical TGFβ signaling pathways to this effect. We then investigated in vitro and in vivo TGFBI impact on metastasis formation and angiogenesis. Using patient serum samples and an orthotopic mouse model of CRC liver metastases we assessed the diagnostic/tumor targeting value of novel antibodies against TGFBI. Results: Metastatic CRC cells, such as circulating tumor cells, directly respond to TGFβ. These cells were characterized by the absence of TGFβ receptor mutations and the frequent presence of p53 mutations. The pro-tumorigenic program orchestrated by TGFβ in CRC cells was mediated through TGFBI, the expression of which was positively regulated by non-canonical TGFβ signaling cascades. TGFBI inhibition was sufficient to significantly reduce liver metastasis formation in vivo. Moreover, TGFBI pro-tumorigenic function was linked to its ability to stimulate angiogenesis. TGFBI levels were higher in serum samples from untreated patients with CRC than in patients who were receiving chemotherapy. A radiolabeled anti-TGFBI antibody selectively targeted metastatic lesions in vivo, underscoring its diagnostic and therapeutic potential. Conclusions: TGFβ signaling in CRC cells directly contributes to their metastatic potential and stromal cell-independence. Proteins downstream of activated TGFβ, such as TGFBI, represent novel diagnostic and therapeutic targets for more specific anti-metastatic therapies.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Chiavarina, Barbara
Costanza, Brunella 
Ronca, Roberto
Blomme, Arnaud  ;  Université de Liège - ULiège > GIGA Stem Cells - Cancer Signaling
Rezzola, Sara
Chiodelli, Paola
Giguelay, Ambre
Belthier, Guillame
Doumont, Gilles
Van Simaeys, Gaetan
Lacroix, Simon
Yokobori, Takehiko
Erkhem-Ochir, Bilguun
Balaguer, Patrick
Cavailles, Vincent
Fabbrizio, Eric
Di Valentin, Emmanuel  ;  Université de Liège - ULiège > Département des sciences de la vie > Virologie - Immunologie
Gofflot, Stéphanie ;  Université de Liège - ULiège > Département des sciences de la santé publique > Département des sciences de la santé publique
Detry, Olivier  ;  Université de Liège - ULiège > Département des sciences cliniques > Pathologie chirurgicale abdominale et endocrinienne
Jerusalem, Guy  ;  Université de Liège - ULiège > Département des sciences cliniques > Oncologie
Goldman, Serge
Delvenne, Philippe ;  Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Anatomie et cytologie pathologiques
Bellahcene, Akeila ;  Université de Liège - ULiège > GIGA Cancer - Metastases Research Laboratory
Pannequin, Julie
More authors (16 more) Less
Language :
Title :
Metastatic colorectal cancer cells maintain the TGFβ program and use TGFBI to fuel angiogenesis.
Publication date :
January 2021
Journal title :
Publisher :
Ivyspring International Publisher, Wyoming, Australia
Volume :
Issue :
Pages :
Peer reviewed :
Peer Reviewed verified by ORBi
Funders :
F.R.S.-FNRS - Fonds de la Recherche Scientifique [BE]
Labex MabImprove
INSERM - Institut National de la Santé et de la Recherche Médicale [FR]
Funding number :
SIRIC Montpellier Cancer Grant INCA_Inserm_DGOS_12553
Available on ORBi :
since 07 May 2021


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