Anti-metastatic potential of somatostatin analog SOM230: Indirect pharmacological targeting of pancreatic cancer-associated fibroblasts

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Published on Monday, 16 May 2016

Abstract

Pancreatic ductal adenocarcinoma (PDA) shows a rich stroma where cancer-associated fibroblasts (CAFs) represent the major cell type. CAFs are master secretors of proteins with pro-tumor features.

CAF targeting remains a promising challenge for PDA, a devastating disease where treatments focusing on cancer cells have failed.

We previously introduced a novel pharmacological CAF-targeting approach using the somatostatin analog SOM230 (pasireotide) that inhibits protein synthesis in CAFs, and subsequent chemoprotective features of CAF secretome.

Using primary cultures of CAF isolated from human PDA resections, we here report that CAF secretome stimulates in vitro cancer cell survival, migration and invasive features, that are abolished when CAFs are treated with SOM230.

Mechanistically, SOM230 inhibitory effect on CAFs depends on the somatostatin receptor subtype sst1 expressed in CAFs but not in non-activated pancreatic fibroblasts, and on protein synthesis shutdown through eiF4E-Binding Protein-1 (4E-BP1) expression decrease.

We identify interleukin-6 as a SOM230-inhibited CAF-secreted effector, which stimulates cancer cell features through phosphoinositide 3-kinase activation.

In vivo, mice orthotopically co-xenografted with the human pancreatic cancer MiaPaCa-2 cells and CAFs develop pancreatic tumors, on which SOM230 treatment does not inhibit growth but abrogates metastasis.

Consistently, CAF secretome stimulates epithelial-to-mesenchymal transition in cancer cells, which is reversed upon CAF treatment with SOM230.

Our results highlight a novel promising anti-metastatic potential for SOM230 indirectly targeting pancreatic cancer cell invasion through pharmacological inhibition of stromal CAFs.

 

 

About this publication.

 

See also:

- Somatostatin in oncology, the overlooked evidences;

- The Di Bella Method Increases by the 30% the survival rate for Pancreas tumors and for this reason should be proposed as first line therapy for this type of cancer.

 


Supplementary Files