OncoTargets and therapy. Dec/31/2017; 11: 5607-5619

Published online Sep/9/2018

PMID: 30254454

PMC: 6141120

doi: 10.2147/OTT.S175566

Podoplanin-positive cancer-associated fibroblasts predict poor prognosis in lung cancer patients

Abstract

Background

Cancer-associated fibroblasts (CAFs) are a heterogeneous population, and different subpopulations play differential roles in tumor microenvironment. However, the prognostic role of podoplanin-positive CAFs in human lung cancer still remains controversial.

Methods

Herein, we performed a meta-analysis including 12 published studies with 1,802 patients identified from PubMed and EBSCO to assess the prognostic impact of podoplanin-positive CAFs in lung cancer patients.

Results

We found that podoplanin⁺ fibroblast infiltration significantly decreased overall survival (OS), disease-free survival (DFS), and progression-free survival in patients. In stratified analyses, podoplanin⁺ fibroblast infiltration was significantly associated with worse OS and DFS in both squamous cell carcinoma and adenocarcinoma of lung. In addition, high density of podoplanin-positive CAFs significantly correlated with unfavorable clinicopathological features such as lymph node metastasis, and lymphatic, vascular, and pleural invasion of patients.

Conclusion

Podoplanin⁺ fibroblast infiltration leads to worse clinical outcome in lung cancer patients, implicating that it is a valuable prognostic biomarker and targeting it may have a potential for effective treatment.

Introduction

Lung cancer is the leading cause of cancer-related death worldwide. Accumulating evidence has demonstrated that tumor-infiltrating fibroblasts (also called cancer-associated fibroblasts [CAFs]) were significantly associated with survival of lung cancer patients. However, CAFs are a heterogeneous population, and hence it is important to distinguish among different subpopulations as they may play differential roles in tumor microenvironment (TME).1 Tumor-infiltrating podoplanin⁺ fibroblasts, a new subset of CAFs identified recently, have been demonstrated to play specific and significant roles in human lung cancer.

Podoplanin, a well-conserved, mucin-type transmembrane protein, has exerted a variety of functions including regulation of organ development and cell motility.2 Recent studies have indicated that podoplanin was often upregulated in CAFs in the tumor stroma.3 Podoplanin⁺ fibroblasts are often among the early immune cells recruited to tumor sites in response to the stimuli and increase in the TME. In the last decades, multitudinous studies have associated podoplanin-positive CAFs and prognosis in lung cancer patients, but their results were controversial.4 Thus, it needs in-depth assessment, and furthermore, the potential of these cells as an effective prognostic biomarker and targeted therapy is necessary to be explored.

Herein, we performed this meta-analysis to clarify the association between podoplanin⁺ fibroblast infiltration and outcomes such as overall survival (OS), disease-free survival (DFS), and progression-free survival (PFS) in lung cancer patients, and thereby provided more evidence on the clinical value of podoplanin-positive CAFs as a prognostic biomarker for lung cancer.

Materials and methods

Search strategy

PubMed and EBSCO were searched for studies to evaluate the density of podoplanin-positive CAFs and survival in lung cancer patients from 1980 to April 15, 2018. The keywords adopted for search were (podoplanin [Title/Abstract] OR fibroblasts [Title/Abstract]) AND (lung [Title/Abstract] OR pulmonary [Title/Abstract]) AND (neoplasms [Title/Abstract] OR tumor [Title/Abstract] OR cancer [Title/ Abstract] OR carcinoma [Title/Abstract]).

Inclusion and exclusion criteria

In this meta-analysis, the inclusion criteria were that studies included must have 1) been published as original articles; 2) investigated lung cancer patients; 3) detected podoplanin⁺ fibroblasts in primary tumor specimens with immunohistochemistry; 4) provided HRs with 95% CI, or Kaplan–Meier curves of podoplanin⁺ fibroblast density associated with OS, and/or DFS, and/or PFS; and 5) been published in English.

We excluded studies that were not published as research articles or were full texts such as commentary, case report, letters to editors, or conference abstracts. Studies that did not provide sufficient data to estimate HRs, or detected fibroblasts without using the marker “podoplanin”, or exhibited metastatic infiltration were also excluded.

End points

In this meta-analysis, OS and DFS were recorded as the primary and PFS as secondary end points. Individual studies defined cut-offs for podoplanin⁺ fibroblast density and classified patients into high- and low-density groups.

Data extraction

The authors GH and KZ independently reviewed and extracted data such as first author’s name, number of patients, median age, time of follow-up, method applied to quantify podoplanin⁺ fibroblasts, and cut-off value to determine high density of these cells. OS, DFS, PFS, and clinicopathological data including TNM stage, and lymphatic, vascular, and pleural invasion were extracted from the text, tables, or Kaplan–Meier curves.

Quality assessment

The studies included in this meta-analysis were cohort studies. Two independent authors assessed the quality of the included studies with Newcastle–Ottawa Scale (NOS),5 and achieved consensus for each item with the help of third author. The studies with score 6 or more were recorded as high-quality studies.

Statistical analysis

We combined extracted data into meta-analyses with STATA 12.0 analysis software (Stata Corporation, College Station, TX, USA). Statistical heterogeneity was assessed with the chi-squared based Q-test or I².6 Data were pooled based on the random-effect model in the presence of heterogeneity,7 otherwise, the fixed-effect model was applied.8 Sensitivity analysis, Begg’s funnel plot, and Egger’s test9 were employed to investigate the influence of each study on the pooled results and potential publication bias, respectively. All P-values were two-sided and values less than 0.05 were considered to be statistically significant.

Result

Search results and description of studies

A total of 9,860 records were retrieved and the results are exhibited in Figure S1. We ultimately identified 12 studies including 1,802 lung cancer patients for the assessment of podoplanin-positive CAFs,10–21 and then evaluated all these studies with the NOS. Characteristics of the included studies which satisfied the inclusion criteria and were suitable for data consolidation are shown in Tables 1 and S1.

Meta-analyses

Overall survival

The meta-analysis showed that the elevated density of podoplanin-positive CAFs was significantly associated with decreased OS (HR=1.66, 95% CI 1.20–2.30, P=0.002) in patients with lung cancer (Figure 1).

In stratified analyses by pathologic types of lung cancer, as shown in Figure 2, pooled results indicated that high density of podoplanin-positive CAFs was significantly associated with worse OS in lung adenocarcinoma (AC) (HR=1.81, 95% CI 1.29–2.53, P=0.001); Similar result was observed with regard to podoplanin-positive CAFs and OS in squamous cell carcinoma (SCC) of lung (HR=2.00, 95% CI 1.27–3.15, P=0.003), with little heterogeneity being observed (I²=31.8%, P=0.231).

Disease-free survival and progression-free survival

Meta-analysis showed that podoplanin⁺ fibroblast infiltration was significantly associated with decreased DFS (HR=1.87, 95% CI 1.07–3.26, P=0.027) and PFS (HR=1.78, 95% CI 1.22–2.58, P=0.002) in lung cancer patients (Figure 3).

As for DFS, in stratified analyses by pathologic types, we found that increased density of podoplanin⁺ fibroblasts within tumor was significantly associated with worse DFS in lung AC (HR=2.52, 95% CI 1.81–3.51, P=0.000), with no heterogeneity existing among included studies (I²=0.0%, P=0.689). Similar result was observed between podoplanin⁺ fibroblast infiltration and DFS in SCC of the lung (HR=2.33, 95% CI 1.45–3.74, P=0.000) (Figure S2).

We further investigated whether podoplanin-positive CAFs correlated with clinicopathological features such as lymph node metastasis and lymphatic invasion of lung cancer. We found that increased density of these cells was significantly associated with lymph node metastasis (OR=1.99, 95% CI 1.35–2.94, P=0.001); lymphatic (OR=2.10, 95% CI 1.06–4.13, P=0.032), vascular (OR=3.83, 95% CI 1.03–14.21, P=0.044), and pleural invasion (OR=2.19, 95% CI 1.03–4.64, P=0.041) (Figure 4); and also with tumor size (OR=0.46, 95% CI 0.32–0.66, P=0.000) and smoking (OR=2.44, 95% CI 1.39–4.27, P=0.002) status, but not with age (dichotomized according to an age of 70 years) (OR=0.81, 95% CI 0.46–1.42, P=0.463) or tumor differentiation (OR=0.24, 95% CI 0.01–4.15, P=0.324) of patients (Figure S3).

Sensitivity analysis

Sensitivity analysis indicated that each included study had no influence on the overall HR for OS or DFS (Figure S4).

Publication bias

There was no publication bias existing between podoplanin-positive CAFs and OS (P=0.876) or DFS (P=0.491) in patients by Funnel plot and Egger’s test.

Discussion

Fibroblasts play a crucial role in maintaining the structural integrity of connective tissues by continuously secreting precursors of the extracellular matrix (ECM). In the past decades, although many studies have correlated podoplanin-positive CAFs with prognosis of lung cancer patients, their results were not consistent but rather controversial. In the present meta-analysis, we found that podoplanin⁺ fibroblast infiltration had a negative prognostic effect associated with survival in lung cancer, especially in AC and SCC of lung. In addition, increased density of podoplanin-positive CAFs was significantly associated with lymph node metastasis; lymphatic, vascular, and pleural invasion; tumor size, and smoking status. We believe that our study is the first to provide meaningful statistical evidence exhibiting the important prognostic value of podoplanin-positive CAFs as a cancer promoter in lung cancer patients.

We thought that the following reasons could possibly be responsible for the close association between increased podoplanin-positive CAFs and decreased survival of patients identified in this study: Activated fibroblasts are able to promote tumor cell invasion, proliferation, and survival through releasing growth factors, cytokines,22 and ECM degrading proteases such as matrix metalloproteinases.23 More importantly, podoplanin expressed in fibroblasts can enhance the ability of these cells to promote motility and survival of neighboring tumor cells through increased RhoA activity, especially in AC cells.24 Podoplanin-positive CAFs can synthesize and release angiogenic factors including IL-8 and TNF-α as well as VEGF which promote neoangiogenesis, thereby facilitating tumor growth.25 In addition, they can also produce varied amounts of immunosuppressive cytokines such as TGF-β1, IL-6, and IL-10 to inhibit antitumor immunity mediated by effector T cells,25 recruit tumor-associated macrophages via CCL2 secretion, and decrease the activation of effector T cells through their acquisition of adhesion molecules such as intercellular adhesion molecule–1 (ICAM-1),26 and thereby establishing immunosuppressive microenvironment. Thus, it is reasonable to conclude that the podoplanin-positive CAFs are able to promote tumor progression, thus decreasing survival. However, one included study reported that the presence of podoplanin-positive CAFs within tumor predicted favorable prognosis in high-grade neuroendocrine carcinomas,14 suggesting that these cells might possess antitumor property. However, further investigation is needed to validate such result.

Previous studies have demonstrated that many cancer types are rich in CAFs, such as pancreatic cancer, and can facilitate a desmoplastic TME, hindering antitumor agents from infiltrating into tumor and thereby dampening treatment efficacy to a greater extent.27 Researchers have developed several therapeutic strategies to target fibroblasts such as nano-delivery of fraxinellone and nanoparticle-mediated trapping of Wnt family member 5A to remodel the TME in preclinical studies, yielding somewhat promising results.28,29 We think our finding may provide a new strategy for effective lung cancer treatment.

There were some limitations in this study. First, morphometric analyses for podoplanin-positive CAFs used in individual included studies were not consistent. Second, there was only one study reporting the relevant data for OS in neuroendocrine carcinomas of the lung; therefore, we could not get a combined result for it. Finally, studies with negative results may not be published, which can cause potential publication bias.

In conclusion, increased density of podoplanin-positive CAFs leads to an unfavorable clinical outcome in lung cancer patients, implicating that it is a valuable prognostic biomarker and targeting it may have a potential for effective treatment.

Supplementary materials

Figure S1

Flowchart diagram of study selection.

ott-11-5607s1.tif

Figure S2

Stratified analyses describing HRs of the association between podoplanin⁺ fibroblast infiltration and DFS.

Abbreviation: DFS, disease-free survival.

ott-11-5607s2.tif

Figure S3

Forest plots indicating ORs of the association between podoplanin⁺ fibroblast infiltration and other clinicopathological features such as tumor size.

Note: Weights are from random-effects analysis.

ott-11-5607s3.tif

Figure S4

Plots describing the influence of individual studies on the overall HRs for OS (A) and DFS (B) in lung cancer patients.

Abbreviations: DFS, disease-free survival; OS, overall survival.

ott-11-5607s4.tif

Table S1

Characteristics of the included studies for OR analysis of clinicopathological features

Study	Year	Tumor type	No of patients	Age (<70/≥70 years)	Podoplanin⁺ fibroblast density: high/low	Lymph node metastasis (yes/no)	Lymphatic invasion (yes/no)	Vascular invasion (yes/no)	Pleural invasion (yes/no)	Tumor size (≤3/>3 cm)	Tumor differentiation (well-moderate/poor)	Smoking (yes/no)
Kubouchi et al2	2018	Stage IA lung adenocarcinoma	158	H: (17/24); L: (55/62)	41/117	NR	H: (18/23); L: (11/106)	NR	NR	NR	H: (29/39); L: (109/8)	H: (30/11); L: (42/75)
Yurugi et al3	2017	Squamous cell carcinoma of lung	126	NR	41/85	H: (11/30); L: (20/65)	H: (4/15); L: (22/63)	NR	H: (22/19); L: (22/63)	H: (14/27); L: (42/43)	NR	H: (39/2); L: (82/3)
Koriyamai et al4	2015	Lung adenocarcinoma	87	NR	30/57	H: (19/11); L: (22/35)	H: (16/14); L: (25/32)	H: (29/1); L: (38/19)	NR	NR	NR	NR
Takahashi et al5	2013	Neuroendocrine carcinomas oflung	115	H: (20/27); L: (41/27)	47/68	NR	NR	NR	H: (14/33); L: (26/42)	NR	NR	NR
Neri et al7	2012	Stage III lung adenocarcinoma	112	NR	51/61	NR	H: (28/23); L: (41/20)	H: (33/18); L: (52/9)	H: (32/19); L: (37/24)	NR	H: (34/14); L: (43/18)	H: (32/19); L: (35/26)
Nakasone et al1	2018	Lung adenocarcinoma	97	NR	40/57	NR	NR	NR	NR	NR	NR	H: (29/11); L: (25/32)
Ito et al8	2012	Stage I lung adenocarcinoma	304	NR	105/199	NR	H: (35/70); L: (20/179)	H: (61/44); L: (23/176)	H: (39/66); L: (20/179)	H: (68/37); L: (161/38)	NR	NR
Kitano et al10	2010	Lung cancer	266	NR	92/174	H: (41/51); L: (64/110)	H: (38/36); L: (78/75)	H: (36/36); L: (46/104)	NR	NR	NR	NR
Kawase et al11	2008	Lung adenocarcinoma	177	H: (40/14); L: (84/39)	54/123	H: (23/31); L: (31/92)	H: (29/25); L: (47/76)	H: (43/11); L: (44/79)	H: (29/25); L: (31/92)	H: (23/31); L: (77/46)	NR	H: (35/19); L: (50/73)

Abbreviations: NR, not reported; H, high; L, low.

References

NakasoneSMimakiSIchikawaTPodoplanin-positive cancer-associated fibroblast recruitment within cancer stroma is associated with a higher number of singlenucleotide variants in cancer cells in lung adenocarcinomaJ Cancer Res Clin Oncol20181445893900

29511884

KubouchiYYurugiYWakaharaMPodoplanin expression in cancer-associated fibroblasts predicts unfavourable prognosis in patients with pathological stage IA lung adenocarcinomaHistopathology2018723490499

28881047

YurugiYWakaharaMMatsuokaYPodoplanin expression in cancer-associated fibroblasts predicts poor prognosis in patients with squamous cell carcinoma of the lungAnticancer Res2017371207214

28011493

KoriyamaiHIshiiGYohKPresence of podoplanin-positive cancer-associated fibroblasts in surgically resected primary lung adenocarcinoma predicts a shorter progression-free survival period in patients with recurrences who received platinum-based chemotherapyJ Cancer Res Clin Oncol2015141711631170

25446816

TakahashiAIshiiGKinoshitaTIdentification of prognostic immunophenotypic features in cancer stromal cells of high-grade neuroendocrine carcinomas of the lungJ Cancer Res Clin Oncol20131391118691878

24013219

OnoSIshiiGNagaiKPodoplanin-positive cancer-associated fibroblasts could have prognostic value independent of cancer cell phenotype in stage I lung squamous cell carcinoma: usefulness of combining analysis of both cancer cell phenotype and cancer-associated fibroblast phenotypeChest20131434963970

23081722

NeriSIshiiGTairaTRecruitment of podoplanin positive cancer-associated fibroblasts in metastatic lymph nodes predicts poor prognosis in pathological N2 stage III lung adenocarcinomaAnn Surg Oncol2012191239533962

22669451

ItoMIshiiGNagaiKMaedaRNakanoYOchiaiAPrognostic impact of cancer-associated stromal cells in patients with stage I lung adenocarcinomaChest20121421151158

22302300

HoshinoAIshiiGItoTPodoplanin-positive fibroblasts enhance lung adenocarcinoma tumor formation: podoplanin in fibroblast functions for tumor progressionCancer Res2011711447694779

21610106

KitanoHKageyamaSHewittSMPodoplanin expression in cancerous stroma induces lymphangiogenesis and predicts lymphatic spread and patient survivalArch Pathol Lab Med20101341015201527

20923309

KawaseAIshiiGNagaiKPodoplanin expression by cancer associated fibroblasts predicts poor prognosis of lung adenocarcinomaInt J Cancer2008123510531059

18546264

Figure 1

Forest plots describing HR of the association between podoplanin⁺ fibroblast infiltration and OS in lung cancer patients.

Note: Weights are from random-effects analysis.

Abbreviation: OS, overall survival.

Figure 2

Stratified analyses describing HRs of the association between podoplanin⁺ fibroblast infiltration and OS.

Note: Weights are from random-effects analysis.

Abbreviation: OS, overall survival.

Figure 3

Forest plots describing HR of the association between podoplanin⁺ fibroblast infiltration and DFS and PFS in lung cancer patients.

Note: Weights are from random-effects analysis.

Abbreviations: DFS, disease-free survival; PFS, progression-free survival.

Figure 4

Forest plots indicating ORs of the association between podoplanin⁺ fibroblast infiltration and clinicopathological features such as lymph node metastasis of lung cancer.

Note: Weights are from random-effects analysis.

Table 1

Main characteristics of the included studies

Study	Year	Tumor type	No of patients	Male/female	Median age (range) (years)	Cut-offs	Podoplanin⁺ fibroblast density: high/low	Tumor stage	Median follow-up date (months)	Survival	Quality score (NOS)
Nakasone et al10	2018	Lung adenocarcinoma	97	51/46	(40, 85)	≥10% of spindle cells in the stroma	40/57	I–III	NR	OS, DFS	6
Kubouchi et al11	2018	Stage IA lung adenocarcinoma	158	76/82	68.8±9.5	≥10% of spindle-shaped cells in the stroma	41/117	IA–IB	82.5 (8, 151)	OS, DFS	7
Yurugi et al12	2017	Squamous cell carcinoma of lung	126	115/11	73.9±8.25	≥10% of spindle-shaped cells in the stroma	41/85	I–IIIA	48.0 (1, 137)	OS, DFS	7
Koriyamai et al13	2015	Lung adenocarcinoma	87	54/33	64 (41, 78)	≥50% of spindle-shaped cells/0.0625 mm²	30/57	I–IV	NR	OS, PFS	6
Takahashi et al14	2013	Neuroendocrine carcinomas of lung	115	98/17	68 (22, 86)	≥50% of spindle-shaped cells/0.0625 mm²	47/68	I–IV	52.8	OS, DFS	8
Ono et al15	2013	Stage I lung squamous cell carcinoma	142	125/17	66 (58, 80)	≥50% of CAFs in the stroma	44/98	IA–IB	62.4	OS, DFS	7
Neri et al16	2012	Stage III lung adenocarcinoma	112	64/48	65.5 (41, 83)	≥10% of stromal fibroblasts/HPF	51/61	III	84	OS	7
Ito et al17	2012	Stage I lung adenocarcinoma	304	139/165	<65: 52%; ≥65: 48%	≥10% of spindle cells in the stroma/0.0625 mm²	105/199	IA–IB	87 (5, 181)	DFS	7
Hoshino et al18	2011	Lung adenocarcinoma	112	54/58	NR	≥10% of spindle cells in the stroma/0.0625 mm²	32/80	NR	≥120	OS, DFS	7
Kitano et al19	2010	Lung adenocarcinoma	157	182/84	65±9.7	≥10% of spindle cells in the stroma/0.0625 mm²	21/79	I–IV	NR	OS	6
		Squamous cell carcinoma of lung	109	182/84	65±9.7	≥10% of spindle cells in the stroma/0.0625 mm²	31/30	I–IV	NR	OS	6
Kawase et al20	2008	Lung adenocarcinoma	177	86/91	<70: 70%; ≥70: 30%	≥10% of spindle cells in the stroma	54/123	I–IV	117.6	OS	8
Yoshida et al21	2015	Lung adenocarcinoma	106	63/43	(42, 85)	≥10% of spindle cells in the stroma	57/49	I–IV	NR	PFS	6

Notes: Values in parenthesis indicate the shortest and longest time to follow up.

Abbreviations: NOS, Newcastle–Ottawa Scale; NR, not reported; CAF, cancer-associated fibroblasts; HPF, high power field; OS, overall survival; DFS, disease-free survival; PFS, progression-free survival.

Footnotes

Author contributions

GH conceived the study, participated in its design, extracted data, performed the statistical analysis, and drafted the manuscript. KZ participated in data extraction. WC and SW participated in the statistical analysis. LH participated in the design of the study. All authors contributed to the paper revision, agreed to be accountable for all aspects of the work and approved the final version. Guoming Hu and Kefang Zhong are co-first authors.

Disclosure

The authors report no conflicts of interest in this work.

Acknowledgments

We thank all the members of the departments who helped in this study. This work was funded by the National Natural Science Foundation of China (Grant No 81702803, GH). This work was partly funded by the projects of Zhejiang Province Scientific Research Foundation of Traditional Chinese Medicine (Grant No 2017ZB089, LH) and Science and Technology Innovation Project of Shaoxing Health and Family Planning Program (Grant No 2016CX002, WC).

References

1. KalluriRThe biology and function of fibroblasts in cancerNat Rev Cancer2016169582598[PubMed][Google Scholar]
2. WickiAChristoforiGThe potential role of podoplanin in tumour invasionBr J Cancer200796115[PubMed][Google Scholar]
3. AstaritaJLActonSETurleySJPodoplanin: emerging functions in development, the immune system, and cancerFront Immunol20123283[PubMed][Google Scholar]
4. PulaBWitkiewiczWDziegielPPodhorska-OkolowMSignificance of podoplanin expression in cancer-associated fibroblasts: a comprehensive reviewInt J Oncol201342618491857[PubMed][Google Scholar]
5. StangACritical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analysesEur J Epidemiol2010259603605[PubMed][Google Scholar]
6. HigginsJPThompsonSGDeeksJJAltmanDGMeasuring inconsistency in meta-analysesBMJ20033277414557560[PubMed][Google Scholar]
7. KuritzSJLandisJRKochGGA general overview of Mantel-Haenszel methods: applications and recent developmentsAnnu Rev Public Health19889123160[PubMed][Google Scholar]
8. DersimonianRKackerRRandom-effects model for meta-analysis of clinical trials: an updateContemp Clin Trials2007282105114[PubMed][Google Scholar]
9. EggerMDavey SmithGSchneiderMMinderCBias in meta-analysis detected by a simple, graphical testBMJ19973157109629634[PubMed][Google Scholar]
10. NakasoneSMimakiSIchikawaTPodoplanin-positive cancer-associated fibroblast recruitment within cancer stroma is associated with a higher number of singlenucleotide variants in cancer cells in lung adenocarcinomaJ Cancer Res Clin Oncol20181445893900[PubMed][Google Scholar]
11. KubouchiYYurugiYWakaharaMPodoplanin expression in cancer-associated fibroblasts predicts unfavourable prognosis in patients with pathological stage IA lung adenocarcinomaHistopathology2018723490499[PubMed][Google Scholar]
12. YurugiYWakaharaMMatsuokaYPodoplanin expression in cancer-associated fibroblasts predicts poor prognosis in patients with squamous cell carcinoma of the lungAnticancer Res2017371207214[PubMed][Google Scholar]
13. KoriyamaiHIshiiGYohKPresence of podoplanin-positive cancer-associated fibroblasts in surgically resected primary lung adenocarcinoma predicts a shorter progression-free survival period in patients with recurrences who received platinum-based chemotherapyJ Cancer Res Clin Oncol2015141711631170[PubMed][Google Scholar]
14. TakahashiAIshiiGKinoshitaTIdentification of prognostic immunophenotypic features in cancer stromal cells of high-grade neuroendocrine carcinomas of the lungJ Cancer Res Clin Oncol20131391118691878[PubMed][Google Scholar]
15. OnoSIshiiGNagaiKPodoplanin-positive cancer-associated fibroblasts could have prognostic value independent of cancer cell phenotype in stage I lung squamous cell carcinoma: usefulness of combining analysis of both cancer cell phenotype and cancer-associated fibroblast phenotypeChest20131434963970[PubMed][Google Scholar]
16. NeriSIshiiGTairaTRecruitment of podoplanin positive cancer-associated fibroblasts in metastatic lymph nodes predicts poor prognosis in pathological N2 stage III lung adenocarcinomaAnn Surg Oncol2012191239533962[PubMed][Google Scholar]
17. ItoMIshiiGNagaiKMaedaRNakanoYOchiaiAPrognostic impact of cancer-associated stromal cells in patients with stage I lung adenocarcinomaChest20121421151158[PubMed][Google Scholar]
18. HoshinoAIshiiGItoTPodoplanin-positive fibroblasts enhance lung adenocarcinoma tumor formation: podoplanin in fibroblast functions for tumor progressionCancer Res2011711447694779[PubMed][Google Scholar]
19. KitanoHKageyamaSHewittSMPodoplanin expression in cancerous stroma induces lymphangiogenesis and predicts lymphatic spread and patient survivalArch Pathol Lab Med20101341015201527[PubMed][Google Scholar]
20. KawaseAIshiiGNagaiKPodoplanin expression by cancer associated fibroblasts predicts poor prognosis of lung adenocarcinomaInt J Cancer2008123510531059[PubMed][Google Scholar]
21. YoshidaTIshiiGGotoKPodoplanin-positive cancer-associated fibroblasts in the tumor microenvironment induce primary resistance to EGFR-TKIs in lung adenocarcinoma with EGFR mutationClin Cancer Res2015213642651[PubMed][Google Scholar]
22. BruzzeseFHägglöfCLeoneALocal and systemic protumorigenic effects of cancer-associated fibroblast-derived GDF15Cancer Res2014741334083417[PubMed][Google Scholar]
23. BoireACovicLAgarwalAJacquesSSherifiSKuliopulosAPAR1 is a matrix metalloprotease-1 receptor that promotes invasion and tumorigenesis of breast cancer cellsCell20051203303313[PubMed][Google Scholar]
24. ItoSIshiiGHoshinoATumor promoting effect of podoplanin-positive fibroblasts is mediated by enhanced RhoA activityBiochem Biophys Res Commun20124221194199[PubMed][Google Scholar]
25. PoggiAMussoADapinoIZocchiMRMechanisms of tumor escape from immune system: role of mesenchymal stromal cellsImmunol Lett20141591–25572[PubMed][Google Scholar]
26. PowellDWMyofibroblasts: paracrine cells important in health and diseaseTrans Am Clin Climatol Assoc2000111271292[PubMed][Google Scholar]
27. MiaoLLiuQLinCMTargeting tumor-associated fibroblasts for therapeutic delivery in desmoplastic tumorsCancer Res2017773719731[PubMed][Google Scholar]
28. LiuQZhuHTiruthaniKNanoparticle-mediated trapping of Wnt family member 5A in tumor microenvironments enhances immunotherapy for B-Raf proto-oncogene mutant melanomaACS Nano201812212501261[PubMed][Google Scholar]
29. HouLLiuQShenLNano-delivery of fraxinellone remodels tumor microenvironment and facilitates therapeutic vaccination in desmoplastic melanomaTheranostics201881437813796[PubMed][Google Scholar]