All-trans-retinoic acid counteract the tumor-stimulating effect of hepatectomy and increases survival of rats bearing liver metastases.
BACKGROUND
We previously demonstrated a stimulating effect of hepatectomy on residual tumor cells after resection of liver metastases. The aim of this study was to analyze the effect of all-trans-retinoic acid (ATRA) on the protumor effect of hepatectomy and survival of hepatectomized rats bearing liver metastases. We also explored whether ATRA interfered with the tumor promoting effect of hepatotropic growth factors (GFs).


METHODS
The in vitro effect of ATRA on proliferation of S4MH rhabdomyosarcoma tumor cells was assessed when cultured with laparotomized or hepatectomized rat serum (HRS), or in the presence of GFs (hepatocyte growth factor, insulin growth factor 2, Platelet Derived Growth Factor (PDGF)-BB, and vascular endothelial growth factor). For the in vivo studies, rats were partially hepatectomized on day 10 after metastasis induction, one group being treated with ATRA from day 7 to 14, and a second receiving cyclophosphamide (CY; on days 10 and 14) alone or with ATRA. We determined the size and number of liver and lung metastases. Finally, we analyzed the effect of treatments on rat survival.


RESULTS
Hepatotropic GFs increased cell proliferation in a similar manner to HRS. In vitro, ATRA blocked the protumor effect of both HRS and GFs. In vivo, ATRA reduced the size and number of liver and lung metastases, and significantly increased rat survival. Furthermore, adding ATRA to CY significantly increased survival compared with CY alone.


CONCLUSIONS
In our model, ATRA minimizes the tumor-stimulating effect of hepatectomy, reducing the number and size of liver metastases and improving survival. The results suggest that the ATRA may be useful for blocking the growth-promoting effect of hepatotropic GFs released after liver metastasis resection.
Department of Surgery and Radiology, University of the Basque Country, Leioa, Spain.
Teodoro
T
Palomares
Department of Surgery and Radiology, University of the Basque Country, Leioa, Spain. Electronic address: ignacio.galonso@ehu.es.
Ignacio
I
García-Alonso
Department of Cell Biology and Histology, University of the Basque Country UPV/EHU, Leioa, Spain.
Roberto
R
San Isidro
Department of Surgery and Radiology, University of the Basque Country, Leioa, Spain.
Jaime
J
Méndez
Department of Cell Biology and Histology, University of the Basque Country UPV/EHU, Leioa, Spain.
Ana
A
Alonso-Varona
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003520:Cyclophosphamide / Q000627:therapeutic use; D006498:Hepatectomy / Q000009:adverse effects*; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D008113:Liver Neoplasms / Q000209:etiology / Q000517:prevention & control*; D008297:Male; D011897:Random Allocation; D051381:Rats; D014212:Tretinoin / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D036341:Intercellular Signaling Peptides and Proteins; D014212:Tretinoin; D003520:Cyclophosphamide
All-trans-retinoic acid; Growth factors; Liver metastasis; Rhabdomyosarcoma; Tumor recurrence