Podoplanin-positive cancer-associated fibroblasts in the tumor microenvironment induce primary resistance to EGFR-TKIs in lung adenocarcinoma with EGFR mutation.
OBJECTIVE
The biologic characteristics of microenvironmental constituents, especially cancer-associated fibroblasts (CAF), can be key regulators of the cellular sensitivity to molecular-targeted therapy. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) have marked therapeutic effects against non-small cell lung cancer (NSCLC) with EGFR mutations, but some patients have exhibited primary resistance to EGFR-TKIs. We recently reported that podoplanin-positive fibroblasts are associated with a tumor-promoting phenotype of CAFs in lung adenocarcinoma. The aim of this study was to evaluate whether the susceptibility of NSCLC to EGFR-TKIs could be affected by podoplanin-expressing CAFs.


METHODS
We evaluated the EGFR-TKI sensitivity of EGFR-mutant lung adenocarcinoma cell lines cocultured with podoplanin-expressing CAFs. We also examined the association between the expression of podoplanin in CAFs in surgical specimens and EGFR-TKI response of postoperative recurrent patients with EGFR mutations (N = 106).


RESULTS
Lung adenocarcinoma cell lines became more resistant to EGFR-TKI when cocultured with podoplanin-expressing CAFs, compared with control CAFs in vitro. The knockdown of podoplanin expression on CAFs cancelled the resistance to EGFR-TKIs in cancer cells. Compared with control CAFs, the cancer cells that were cocultured with podoplanin-positive CAFs continued to exhibit significantly higher p-ERK levels after treatment with gefitinib. Furthermore, postoperative recurrent patients with podoplanin-positive CAFs had a significantly lower overall response rate to EGFR-TKIs compared with those with podoplanin-negative CAFs (53% vs. 83%; P < 0.01).


CONCLUSIONS
Podoplanin-positive CAFs play an important role in primary resistance to EGFR-TKIs and may be an ideal therapeutic target for use in combination therapy with EGFR-TKIs.
Division of Pathology, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan. Division of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan. Department of Medical Oncology and Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan.
Tatsuya
T
Yoshida
Division of Pathology, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan. gishii@east.ncc.go.jp.
Genichiro
G
Ishii
Division of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.
Koichi
K
Goto
Division of Pathology, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.
Shinya
S
Neri
Division of Pathology, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.
Hiroko
H
Hashimoto
Division of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.
Kiyotaka
K
Yoh
Division of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.
Seiji
S
Niho
Division of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.
Shigeki
S
Umemura
Division of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.
Shingo
S
Matsumoto
Division of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.
Hironobu
H
Ohmatsu
Department of Medical Oncology and Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan.
Shinsuke
S
Iida
Department of Medical Oncology and Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan.
Akio
A
Niimi
Division of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.
Kanji
K
Nagai
Division of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.
Yuichiro
Y
Ohe
Division of Pathology, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.
Atsushi
A
Ochiai
D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D000077192:Adenocarcinoma of Lung; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018920:Coculture Techniques; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D000077156:Gefitinib; D015870:Gene Expression; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D010766:Phosphorylation; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use; D012307:Risk Factors; D016896:Treatment Outcome; D059016:Tumor Microenvironment / Q000235:genetics*; D000098853:Podoplanin
D000970:Antineoplastic Agents; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D000077156:Gefitinib; D008562:Membrane Glycoproteins; D051057:Proto-Oncogene Proteins c-akt; D011799:Quinazolines; C117468:PDPN protein, human; D000098853:Podoplanin