TGFBI expression is associated with a better response to chemotherapy in NSCLC.
BACKGROUND
Lung cancer is one of the most prevalent neoplasias in developed countries. Advances in patient survival have been limited and the identification of prognostic molecules is needed. Resistance to treatment is strongly related to tumor cell adhesion to the extracellular matrix and alterations in the quantity and nature of molecules constituting the tumor cell niche. Recently, transforming growth factor beta-induced protein (TGFBI), an extracellular matrix adaptor protein, has been reported to be differentially expressed in transformed tissues. Loss of TGFBI expression has been described in several cancers including lung carcinoma, and it has been suggested to act as a tumor suppressor gene.


RESULTS
To address the importance of TGFBI expression in cancer progression, we determined its expression in NSCLC clinical samples using immunohistochemistry. We identified a strong association between elevated TGFBI expression and the response to chemotherapy. Furthermore, we transiently over-expressed and silenced TGFBI in human NSCLC cell lines. Cells over-expressing TGFBI displayed increased sensitivity to etoposide, paclitaxel, cisplatin and gemcitabine. We observed that TGFBI-mediated induction of apoptosis occurred through its binding to alphavbeta3 integrin. We also determined that full-length TGFBI did not induce caspase 3/7 activation but its proteolytic fragments that were < 3 kDa in size, were able to activate caspase 3, 7 and 8. This pro-apoptotic effect was blocked by anti-alphavbeta3 integrin antibodies.


CONCLUSIONS
The results shown here indicate that TGFBI is a predictive factor of the response to chemotherapy, and suggest the use of TGFBI-derived peptides as possible therapeutic adjuvants for the enhancement of responses to chemotherapy.
Division of Oncology, Center for Applied Medical Research, Universidad de Navarra, Pío XII 55, Pamplona, 31008, Spain.
Marta
M
Irigoyen
María J
MJ
Pajares
Jackeline
J
Agorreta
Mariano
M
Ponz-Sarvisé
Elisabeth
E
Salvo
María D
MD
Lozano
Ruben
R
Pío
Ignacio
I
Gil-Bazo
Ana
A
Rouzaut
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D020169:Caspases / Q000378:metabolism; D004789:Enzyme Activation; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D011379:Prognosis; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D000099222:betaIG-H3 Protein
D000970:Antineoplastic Agents; D020169:Caspases; D016326:Extracellular Matrix Proteins; D016212:Transforming Growth Factor beta; D000099222:betaIG-H3 Protein