Metastatic colorectal cancer cells maintain the TGFβ program and use TGFBI to fuel angiogenesis
Gespeichert in:
| Titel: | Metastatic colorectal cancer cells maintain the TGFβ program and use TGFBI to fuel angiogenesis |
|---|---|
| Autoren: | Chiavarina, Barbara, Costanza, Brunella, Ronca, Roberto, Blomme, Arnaud, Rezzola, Sara, Chiodelli, Paola, Giguelay, Ambre, Belthier, Guillaume, Doumont, Gilles, van Simaeys, Gaetan, Lacroix, Simon, Yokobori, Takehiko, Erkhem-Ochir, Bilguun, Balaguer, Patrick, Cavaillès, Vincent, Fabbrizio, Eric, Di Valentin, Emmanuel, Gofflot, Stephanie, Detry, Olivier, Jerusalem, Guy, Goldman, Serge, Delvenne, Philippe, Bellahcène, Akeila, Pannequin, Julie, Castronovo, Vincent, Turtoi, Andrei |
| Weitere Verfasser: | F.R.S.-FNRS - Fonds de la Recherche Scientifique, Labex MabImprove, INSERM - Institut National de la Santé et de la Recherche Médicale, UM, Faculté de Médecine |
| Quelle: | Theranostics Theranostics, 11 (4 |
| Verlagsinformationen: | Ivyspring International Publisher, 2021. |
| Publikationsjahr: | 2021 |
| Schlagwörter: | 0301 basic medicine, Colorectal Neoplasms -- blood supply -- metabolism -- pathology, Endothelial cells, Oncologie, Apoptosis, alternative TGFβ signaling, Liver Neoplasms -- blood supply -- metabolism -- secondary, Liver metastases, Mice, Cell Movement, Transforming Growth Factor beta, Tumor Cells, Cultured, Human health sciences, Extracellular Matrix Proteins, 0303 health sciences, Cultured, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Neovascularization, Pathologic, Tumor -- genetics -- metabolism, Liver Neoplasms, Sciences bio-médicales et agricoles, Prognosis, Life sciences, endothelial cells, Tumor Cells, 3. Good health, Gene Expression Regulation, Neoplastic, Oncology, Neovascularization, Pathologic -- metabolism -- pathology, Sciences du vivant, Colorectal Neoplasms, Research Paper, Signal Transduction, Extracellular Matrix Proteins -- genetics -- metabolism, Alternative TGFβ signaling, Biochimie, biophysique & biologie moléculaire, Sciences de la santé humaine, 03 medical and health sciences, Biomarkers, Tumor, Animals, Humans, Neovascularization, Cell Proliferation, Neoplastic, Pathologic -- metabolism -- pathology, Transforming Growth Factor beta -- genetics -- metabolism, Xenograft Model Antitumor Assays, Gene Expression Regulation, Sciences pharmaceutiques, liver metastases, Biomarkers, Biomarkers, Tumor -- genetics -- metabolism, Biochemistry, biophysics & molecular biology |
| Beschreibung: | 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. |
| Publikationsart: | Article Other literature type |
| Dateibeschreibung: | application/pdf; 2 full-text file(s): application/pdf |
| Sprache: | English |
| ISSN: | 1838-7640 |
| DOI: | 10.7150/thno.51507 |
| Zugangs-URL: | https://pubmed.ncbi.nlm.nih.gov/33408771 https://hal.umontpellier.fr/hal-03106867/document https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7778592 https://orbi.uliege.be/handle/2268/259730 https://pubmed.ncbi.nlm.nih.gov/33408771/ https://hal.umontpellier.fr/hal-03106867 https://www.thno.org/v11p1626.htm https://hdl.handle.net/2268/259730 https://doi.org/10.7150/thno.51507 https://hal.umontpellier.fr/hal-03106867v1 https://hal.umontpellier.fr/hal-03106867v1/document https://doi.org/10.7150/thno.51507 http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/319061 https://hdl.handle.net/10807/229402 https://doi.org/10.7150/thno.51507 |
| Rights: | CC BY NC CC BY |
| Dokumentencode: | edsair.doi.dedup.....60e9c7e07d3bd95c7beefaf9ee1bc4f3 |
| Datenbank: | OpenAIRE |
Full Text 
Full Text Finder 
Nájsť tento článok vo Web of Science | Abstract: | 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. |
|---|---|
| ISSN: | 18387640 |
| DOI: | 10.7150/thno.51507 |