P4HA1 regulates human colorectal cancer cells through HIF1α-mediated Wnt signaling

Colorectal cancer (CRC) is the third most commonly diagnosed malignancy that is associated with high levels of mortality. CRCs are often associated with an aberrant wingless-type mouse mammary tumor virus integration site family (Wnt) signaling pathway known to be responsible for tumorigenesis and cancer progression. Other factors that contribute to CRC pathology include hypoxia, extracellular matrix and cellular microenvironment. In the present study, modulation of Wnt, a common molecular progenitor for CRC-associated pathology was evaluated. CRC tissues and specific cell lines were found to exhibit increased expression levels of prolyl 4-hydroxylase subunit α1 (P4HA1). P4HA1 expression was found to stabilize hypoxia inducible factor-1α (HIF1α). The silencing of P4HA1 resulted in decreased cell proliferation, cell cycle arrest in the G₁ phase, decreased tumorsphere formation, decreased tumorsphere volume, increased susceptibility to 5-fluorouracil and increased caspase-3 activity. However, P4HA1 silencing resulted in the activation and thus proteasomal degradation of β-catenin, indicative of the abrogation of Wnt signaling pathway. Wnt is a critical signaling pathway and is activated in most CRCs. HIF1α is a poor prognostic marker in CRC. The present study provided preliminary evidence that HIF1α and the Wnt signaling pathway in CRC are modulated through P4HA1. P4HA1 may serve not just as a biomarker for CRC prognosis but may also be targeted for potential therapeutic intervention.     

Activated macrophages promote invasion by early colorectal cancer via an interleukin 1β‐serum amyloid A1 axis

Submucosal invasion and lymph node metastasis are important issues affecting treatment options for early colorectal cancer (CRC). In this study, we aimed to unravel the molecular mechanism underlying the invasiveness of early CRCs. We performed RNA‐sequencing (RNA‐seq) with poorly differentiated components (PORs) and their normal counterparts isolated from T1 CRC tissues and detected significant upregulation of serum amyloid A1 (SAA1) in PORs. Immunohistochemical analysis revealed that SAA1 was specifically expressed in PORs at the invasive front of T1b CRCs. Upregulation of SAA1 in CRC cells promoted cell migration and invasion. Coculture experiments using CRC cell lines and THP‐1 cells suggested that interleukin 1β (IL‐1β) produced by macrophages induces SAA1 expression in CRC cells. Induction of SAA1 and promotion of CRC cell migration and invasion by macrophages were inhibited by blocking IL‐1β. These findings were supported by immunohistochemical analysis of primary T1 CRCs showing accumulation of M1‐like/M2‐like macrophages at SAA1‐positive invasive front regions. Moreover, SAA1 produced by CRC cells stimulated upregulation of matrix metalloproteinase‐9 in macrophages. Our data suggest that tumor‐associated macrophages at the invasive front of early CRCs promote cancer cell migration and invasion through induction of SAA1 and that SAA1 may be a predictive biomarker and a useful therapeutic target.     

Angiogenic activities are increased via upregulation of HIF-1α expression in gefitinib-resistant non-small cell lung carcinoma cells

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) have been used to treat patients with non-small cell lung cancer (NSCLC) and activating EGFR mutations; however, the emergence of secondary mutations in EGFR or the acquisition of resistance to EGFR-TKIs can develop and is involved in clinical failure. Since angiogenesis is associated with tumor progression and the blockade of antitumor drugs, inhibition of angiogenesis could be a rational strategy for developing anticancer drugs combined with EGFR-TKIs to treat patients with NSCLC. The signaling pathway mediated by hypoxia-inducible factor-1 (HIF-1) is essential for tumor angiogenesis. The present study aimed to identify the dependence of gefitinib resistance on HIF-1α activity using angiogenesis assays, western blot analysis, colony formation assay, xenograft tumor mouse model and immunohistochemical analysis of tumor tissues. In the NSCLC cell lines, HIF-1α protein expression levels and hypoxia-induced angiogenic activities were found to be increased. In a xenograft mouse tumor model, tumor tissues derived from gefitinib-resistant PC9 cells showed increased protein expression of HIF-1α and angiogenesis within the tumors. Furthermore, inhibition of HIF-1α suppressed resistance to gefitinib, whereas overexpression of HIF-1α increased resistance to gefitinib. The results from the present study provides evidence that HIF-1α was associated with the acquisition of resistance to gefitinib and suggested that inhibiting HIF-1α alleviated gefitinib resistance in NSCLC cell lines.     

The prognostic value of tumour-stroma ratio in triple-negative breast cancer

Background

Triple-negative cancer constitutes one of the most challenging groups of breast cancer given its aggressive clinical behaviour, poor outcome and lack of targeted therapy. Until now, profiling techniques have not been able to distinguish between patients with a good and poor outcome. Recent studies on tumour-stroma, found it to play an important role in tumour growth and progression.

Objective

To evaluate the prognostic value of the tumour-stroma ratio (TSR) in triple-negative breast cancer.

Methods

One hundred twenty four consecutive triple-negative breast cancer patients treated in our hospital were selected and evaluated. For each patient the Haematoxylin-Eosin (H&E) stained histological sections were evaluated for percentage of stroma. Patients with less than 50% stroma were classified as stroma-low and patients with ≥50% stroma were classified as stroma-high.

Results

Of 124 triple-negative breast cancer patients, 40% had a stroma-high and 60% had a stroma-low tumour. TSR was assessed by two investigators (kappa 0.74). The 5-years relapse-free period (RFP) and overall survival (OS) were 85% and 89% in the stroma-low and 45% and 65% in the stroma-high group. In a multivariate cox-regression analysis, stroma amount remained an independent prognostic variable for RFP (HR 2.39; 95% CI 1.07–5.29; p = 0.033) and OS (HR 3.00; 95% CI 1.08–8.32; 0.034).

Conclusion

TSR is a strong independent prognostic variable in triple-negative breast cancer. It is simple to determine, reproducible and can be easily incorporated into routine histological examination. This parameter can help optimize risk stratification and might lead to future targeted therapies.     

肿瘤间质比及肿瘤浸润性淋巴细胞对晚期结直肠癌的预后价值

目的:研究结直肠癌肿瘤间质比（tumor-stromaratio ,TSR ）及肿瘤浸润性淋巴细胞（tumor-infiltratinglymphocytes,TIL）与结直肠癌患者的预后相关性。方法:收集浙江大学医学院附属第二医院病理科2007年1 月至2009年12月手术切除的原发性Ⅱ、Ⅲ期结直肠癌218 例病理资料进行回顾性分析,通过HE染色评估肿瘤组织中间质成分所占比例及淋巴细胞浸润情况,并分析不同分组对患者预后生存的影响。结果:218 例Ⅱ、Ⅲ期结直肠癌患者中低TSR 组总体生存率明显高于高间质组（P<0.05）。TSR 与各项临床特征及病理指标,如性别、年龄等无关（P>0.05）。TSR 及TIL 均为Ⅱ、Ⅲ期结直肠癌患者的独立预后因子。高淋巴细胞浸润组患者总体生存率明显高于低淋巴细胞浸润组患者,在低间质组中高淋巴细胞浸润组的患者总体生存率高于低淋巴细胞浸润组患者（P<0.05）。 结论:肿瘤间质比及肿瘤浸润性淋巴细胞对结直肠癌预后均相关,在常规病理诊断中通过对这两项指标的综合评估,可作为辅助指标对结直肠癌患者的预后预测、临床治疗选择提供依据。      

Expression of human leukocyte antigen class I and β2‐microglobulin in colorectal cancer and its prognostic impact

Downregulation of human leukocyte antigen (HLA) class I has been postulated to be a mechanism of adaptive immune escape in various tumors, especially microsatellite instability–high (MSI‐H) colorectal cancer (CRC). In this study, we aimed to investigate HLA class I and β2‐microglobulin (β2M) expression in MSI‐H and microsatellite‐stable (MSS) CRCs and determine its prognostic impact. The representative areas from the tumor center (TC) and tumor periphery (TP) from 300 CRCs, including 161 MSI‐H and 139 MSS cases, were selected to construct a tissue microarray. Immunohistochemistry (IHC) for HLA A/B/C, β2M, CD3, and CD8 was performed. Reduced HLA A/B/C expression was detected in 113 (70.2%) MSI‐H and 54 (38.8%) MSS cases, while reduced β2M expression was observed in 69 (42.9%) MSI‐H and 17 (12.2%) MSS cases. Although reduced β2M expression was associated with higher pathological tumor (pT) stage in MSI‐H CRC with borderline significance, no association was found between HLA A/B/C and β2M expression and survival. Interestingly, reduced HLA A/B/C expression in MSS was associated with higher stage, and reduced HLA A/B/C and β2M expression was an independent prognostic factor in multivariate analysis. In conclusion, reduced HLA A/B/C and β2M expression was frequently observed in immunotherapy‐naive MSI‐H CRC, suggesting the possibility of primary resistance to immune checkpoint inhibitor. Interestingly, downregulation of HLA A/B/C and β2M was associated with poor prognosis in MSS cancers. Overall, IHC for HLA A/B/C and β2M might be a feasible predictive or prognostic tool in CRC.     

VHH212 nanobody targeting the hypoxia-inducible factor 1α suppresses angiogenesis and potentiates gemcitabine therapy in pancreatic cancer in vivo

Objective:We aimed to develop a novel anti-HIF-1α intrabody to decrease gemcitabine resistance in pancreatic cancer patients.Methods:Surface plasmon resonance and glutathione S-transferase pull-down assays were conducted to identify the binding affinity and specificity of anti-HIF-1α VHH212 [a single-domain antibody (nanobody)]. Molecular dynamics simulation was used to determine the protein-protein interactions between hypoxia-inducible factor-1α (HIF-1α) and VHH212. The real-time polymerase chain reaction (PCR) and Western blot analyses were performed to identify the expressions of HIF-1α and VEGF-A in pancreatic ductal adenocarcinoma cell lines. The efficiency of the VHH212 nanobody in inhibiting the HIF-1 signaling pathway was measured using a dual-luciferase reporter assay. Finally, a PANC-1 xenograft model was developed to evaluate the anti-tumor efficiency of combined treatment. Immunohistochemistry analysis was conducted to detect the expressions of HIF-1α and VEGF-A in tumor tissues.Results:VHH212 was stably expressed in tumor cells with low cytotoxicity, high affinity, specific subcellular localization, and neutralization of HIF-1α in the cytoplasm or nucleus. The binding affinity between VHH212 and the HIF-1α PAS-B domain was 42.7 nM. Intrabody competitive inhibition of the HIF-1α heterodimer with an aryl hydrocarbon receptor nuclear translocator was used to inhibit the HIF-1/VEGF pathway in vitro. Compared with single agent gemcitabine, co-treatment with gemcitabine and a VHH212-encoding adenovirus significantly suppressed tumor growth in the xenograft model with 80.44% tumor inhibition.Conclusions:We developed an anti-HIF-1α nanobody and showed the function of VHH212 in a preclinical murine model of PANC-1 pancreatic cancer. The combination of VHH212 and gemcitabine significantly inhibited tumor development. These results suggested that combined use of anti-HIF-1α nanobodies with first-line treatment may in the future be an effective treatment for pancreatic cancer.     

Mitochondrial malic enzyme 2 promotes breast cancer metastasis via stabilizing HIF-1α under hypoxia

Objectiveα-ketoglutarate (α-KG) is the substrate to hydroxylate collagen and hypoxia-inducible factor-1α (HIF-1α), which are important for cancer metastasis. Previous studies have shown that the upregulation of collagen prolyl 4-hydroxylase in breast cancer cells stabilizes the expression of HIF-1α by depleting α-KG levels. We hypothesized that mitochondrial malic enzyme 2 (ME2) might also affect HIF-1α expression via modulating α-KG levels in breast cancer cells.MethodsWe evaluated ME2 protein expression in 100 breast cancer patients using immunohistochemistry and correlated with clinicopathological indicators. The effect of ME2 knockout on cancer metastasis was evaluated using an orthotopic breast cancer model. The effect of ME2 knockout or knockdown on the levels of α-KG and HIF-1α proteins in breast cancer cell lines was determined both in vitro and in vivo. ResultsME2 was found to be upregulated in the human breast cancerous tissues compared with the matched precancerous tissues (P<0.001). The elevated expression of ME2 was associated with a poor prognosis (P=0.019). ME2 upregulation was also related to lymph node metastasis (P=0.016), pathological staging (P=0.033), and vascular cancer embolus (P=0.014). Also, ME2 knockout significantly inhibited lung metastasisin vivo. In the tumors formed by ME2 knockout cells, the levels of α-KG were significantly increased and collagen hydroxylation level did not change significantly but HIF-1α protein expression was significantly decreased, compared to the control samples. In cell culture, cells with ME2 knockout or knockdown demonstrated significantly higher α-KG levels but significantly lower HIF-1α protein expression than control cells under hypoxia. Exogenous malate and α-KG exerted similar effect on HIF-1α in breast cancer cells to ME2 knockout or knockdown. Additionally, treatment with malate significantly decreased 4T1 breast cancer lung metastasis. ME2 expression was associated with HIF-1α levels in human breast cancer samples (P=0.008). ConclusionsOur results provide evidence that upregulation of ME2 is associated with a poor prognosis of breast cancer patients and propose a mechanistic understanding of a link between ME2 and breast cancer metastasis.     

Triple therapy with osimertinib,bevacizumab and cetuximab in EGFR-mutant lung cancer with HIF-1α/TGF-α expression

Osimertinib, a third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is the standard treatment for patients with lung cancer harboring EGFR T790M; however, acquired resistance is inevitable due to genetic and epigenetic changes in cancer cells. In addition, a recent randomized clinical trial revealed that the combination of osimertinib and bevacizumab failed to exhibit superior progression-free survival compared with osimertinib alone. The present study aimed to investigate the effect of triple therapy with osimertinib, bevacizumab and cetuximab in xenograft tumors with different initial tumor volumes (conventional model, 200 mm³ and large model, 500 mm³). The results demonstrated that osimertinib significantly inhibited tumor growth in both the conventional and large models; however, maximum tumor regression was attenuated in the large model in which hypoxia-inducible factor-1α (HIF-1α) and transforming growth factor-α (TGF-α) expression levels increased. Although the combination of osimertinib and bevacizumab exerted a greater inhibitory effect on tumor growth compared with osimertinib in the conventional model, the effect of this combination therapy was attenuated in the large model. TGF-α attenuated sensitivity to osimertinib in vitro; however, this negative effect was counteracted by the combination of osimertinib and cetuximab, but not osimertinib and bevacizumab. In the large xenograft tumor model, the triple therapy induced the greatest inhibitory effect on tumor growth compared with osimertinib alone and its combination with bevacizumab. Clinical trials of the triple therapy are required for patients with lung cancer with EGFR mutations and HIF-1α/TGF-α.     

The prognostic value of the tumor–stroma ratio is most discriminative in patients with grade III or triple-negative breast cancer

The tumor–stroma ratio (TSR) was evaluated as a promising parameter for breast cancer prognostication in clinically relevant subgroups of patients. The TSR was assessed on hematoxylin and eosin-stained tissue slides of 1,794 breast cancer patients from the Nottingham City Hospital. An independent second cohort of 737 patients from the Netherlands Cancer Institute to Antoni van Leeuwenhoek was used for evaluation. In the Nottingham Breast Cancer series, the TSR was an independent prognostic parameter for recurrence-free survival (RFS; HR 1.35, 95% CI 1.10–1.66, p = 0.004). The interaction term was statistically significant for grade and triple-negative status. Multivariate Cox regression analysis showed a more pronounced effect of the TSR for RFS in grade III tumors (HR 1.89, 95% CI 1.43–2.51, p < 0.001) and triple-negative tumors (HR 1.86, 95% CI 1.10–3.14, p = 0.020). Comparable hazard ratios and confidence intervals were observed for grade and triple-negative status in the ONCOPOOL study. The prognostic value of TSR was not modified by age, tumor size, histology, estrogen receptor status, progesterone receptor status, human epidermal growth factor receptor 2 status or lymph node status. In conclusion, patients with a stroma-high tumor had a worse prognosis compared to patients with a stroma-low tumor. The prognostic value of the TSR is most discriminative in grade III tumors and triple-negative tumors. The TSR was not modified by other clinically relevant parameters making it a potential factor to be included for improved risk stratification.     

Are disseminated tumor cells in bone marrow and tumor-stroma ratio clinically applicable for patients undergoing surgical resection of primary colorectal cancer? The Leiden MRD study

Purpose

Current TNM staging does not appropriately identify high-risk colorectal cancer (CRC) patients. The aim of this study was to evaluate whether the presence of disseminated tumor cells (DTCs) in the bone marrow (BM) and the presence of stroma in the primary tumor, i.e., the tumor-stroma ratio (TSR), in patients undergoing surgical resection of primary CRC provides information relevant for disease outcome.

Methods

Patients with primary CRC (n?=?125), consecutively admitted for curative resection between 2001 and 2007, were included in the study. All patients underwent BM aspiration before surgery. Detection of tumor cells was performed using immunocytochemical staining for cytokeratin (CK-ICC). The TSR was determined on diagnostic H&E stained sections of primary tumors.

Results

DTCs were detected in the BM of 23/125 patients (18 %). No association was found between BM status and overall survival (HR 0.97 (95 % CI 0.45–2.09), p?=?0.93). Also, no significant difference was found in their 5-year survival rate (resp. 72 % and 68 % for BM-positive versus BM-negative patients). The TSR was found to be associated with a worse overall survival (HR 2.16, 95 % CI 1.02–4.57, p?=?0.04) with 5-year survival rates of 84 % versus 62 % for stroma-low and stroma-high patients, respectively. No relation was found between the presence of DTCs and TSR.

Conclusions

Our data indicate that the presence of DTCs in the BM of CRC patients is not associated with disease outcome. The TSR was, however, found to be associated with a worse overall survival, which indicates that for CRC the tumor microenvironment plays an important role in its behavior and prognosis.

     

Identification of Smurf2 as a HIF-1α degrading E3 ubiquitin ligase

The major adaptive response to hypoxia involves hypoxia-inducible factor HIF-1α which is regulated by von Hippel Lindau (VHL) E3 ligase. We previously observed a stabilization of HIF-1α by cyclin-dependent kinases CDK1 and CDK4/6 that is independent of VHL, hypoxia or p53, and found that CDK4/6 inhibitors destabilize HIF-1α under normoxia and hypoxia. To further investigate the molecular mechanism of HIF-1α destabilization by CDK1 or CDK4/6 inhibitors, we performed a proteomic screen on immunoprecipitated HIF-1α from hypoxic colorectal cancer cells that were either untreated or treated with CDK1 inhibitor Ro3306 and CDK4/6 inhibitor palbociclib. Our proteomics screen identified a number of candidates that were enriched in palbociclib-treated hypoxic cells including SMAD specific E3 ubiquitin protein ligase 2 (Smurf2). We also identified a HIF-1α peptide that appeared to be differentially phosphorylated after palbociclib treatment. Gene knockdown of SMURF2 increased basal expression of HIF-1α even in the presence of Ro3306 or two different CDK4/6 inhibitors, palbociclib and abemaciclib. Overexpression of Smurf2 inhibited expression of HIF-1α and enhanced HIF-1α ubiquitination in normoxia. Proteasome inhibitor MG-132 partially rescued HIF-1α expression when Smurf2 was overexpressed. Smurf2 overexpression also inhibited HIF-1α expression level in two other cell lines, SW480 and VHL-deficient RCC4. Overexpression of SMURF2 mRNA is correlated with improved disease-free survival and overall survival in clear cell renal cell cancer. Our results unravel a previously unknown mechanism involving Smurf2 for HIF-1α destabilization in CDK4/6 inhibitor-treated cells, thereby shedding light on VHL-independent HIF-1α regulation.     

HIF-1α effects on angiogenic potential in human small cell lung carcinoma

Background

Hypoxia-inducible factor-1 alpha (HIF-1α) maybe an important regulatory factor for angiogenesis of small cell lung cancer (SCLC). Our study aimed to investigate the effect of HIF-1α on angiogenic potential of SCLC including two points: One is the effect of HIF-1α on the angiogenesis of SCLC in vivo. The other is the regulation of angiogenic genes by HIF-1α in vitro and in vivo.

Methods

In vivo we used an alternative method to study the effect of HIF-1a on angiogenic potential of SCLC by buliding NCI-H446 cell transplantation tumor on the chick embryo chorioallantoic membrane (CAM) surface. In vitro we used microarray to screen out the angiogenic genes regulated by HIF-1a and tested their expression level in CAM transplantation tumor by RT-PCR and Western-blot analysis.

Results

In vivo angiogenic response surrounding the SCLC transplantation tumors in chick embryo chorioallantoic membrane (CAM) was promoted after exogenous HIF-1α transduction (p < 0.05). In vitro the changes of angiogenic genes expression induced by HIF-1α in NCI-H446 cells were analyzed by cDNA microarray experiments. HIF-1α upregulated the expression of angiogenic genes VEGF-A, TNFAIP6, PDGFC, FN1, MMP28, MMP14 to 6.76-, 6.69-, 2.26-, 2.31-, 4.39-, 2.97- fold respectively and glycolytic genes GLUT1, GLUT2 to2.98-, 3.74- fold respectively. In addition, the expression of these angiogenic factors were also upregulated by HIF-1α in the transplantion tumors in CAM as RT-PCR and Western-blot analysis indicated.

Conclusions

These results indicated that HIF-1α may enhance the angiogenic potential of SCLC by regulating some angiogenic genes such as VEGF-A, MMP28 etc. Therefore, HIF-1α may be a potential target for the gene targeted therapy of SCLC.     

Effect of isoform-specific HIF-1α and HIF-2α antisense oligonucleotides on tumorigenesis,inflammation and fibrosis in a hepatocellular carcinoma mouse model

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. For advanced HCC, there is still an unmet need for more effective therapeutic strategies. HCC is typically associated with hypoxia and the hypoxia-inducible factor (HIF) regulatory pathway plays an important role in HCC development and progression. Therefore, we investigated the therapeutic potential of isoform-specific HIF-1α and HIF-2α antisense oligonucleotides (ASOs), along with their effect on the inflammatory and fibrotic component of the tumor microenvironment (TME), in an experimental HCC mouse model. Based on its efficacy and safety, a dosage regimen of 20 mg/kg intraperitoneal injection of HIFα ASO twice per week was selected for further investigation in a preventive and therapeutic setting in a N,N-diethylnitrous amide (DEN)-induced HCC mouse model. DEN administration resulted in 100% tumor formation and HIFα ASO administration led to effective and selective hepatic downregulation of its target genes. HIFα ASO treatment had no effect on tumor numbers, but even enhanced the increased hepatic expression of HCC tumor markers, α-fetoprotein and glypican-3, compared to scrambled control ASO treatment in HCC mice. Especially HIF-1α ASO treatment resulted in an enhanced increase of monocytes and monocyte-derived macrophages in the liver and an enhanced hepatic upregulation of inflammatory markers. Both HIFα ASOs aggravated liver fibrosis in HCC mice compared to scrambled ASO treatment. The observed effects of our dosing regimen for HIF-1α and HIF-2α ASO treatment in the DEN-induced HCC mouse model discourage the use of HIFα isoforms as targets for the treatment of HCC.     

Metformin suppresses hypoxia-induced stabilization of HIF-1α through reprogramming of oxygen metabolism in hepatocellular carcinoma

Overexpression of hypoxia-induced factor 1α (HIF-1α) has been shown to be involved in the development and progression of hepatocellular carcinoma (HCC). HIF-1α should therefore be a promising molecular target for the development of anti-HCC agents. Metformin, an established antidiabetic drug, has proved to also be effective in treating cancer although the precise underlying mechanisms of this activity are not fully elucidated. The aim of this study was to investigate the effects of metformin on the expression of HIF-1α and oxygen metabolism in HCC. The results showed that metformin inhibited hypoxia-induced HIF-1α accumulation and activation independent of AMP-activated protein kinase (AMPK). Moreover, this decrease in HIF-1α accumulation was accompanied by promotion of HIF-1α protein degradation. In addition, metformin significantly decreased oxygen consumption, ultimately leading to increased intracellular oxygen tension and decreased staining with the hypoxia marker pimonidazole. In vivo studies demonstrated that metformin delayed tumor growth and attenuated the expression of HIF-1α in HCC tumor xenografts. Together, these findings suggest that metformin decreases hypoxia-induced HIF-1α accumulation by actively suppressing mitochondrial oxygen consumption and enhancing cellular oxygenation ability, providing a fundamental mechanism of metformin activity against HCC.     

Cancer‐associated fibroblast migration in non‐small cell lung cancers is modulated by increased integrin α11 expression

Cancer‐associated fibroblasts (CAFs) regulate cancer progression through the modulation of extracellular matrix (ECM) and cancer cell adhesion. While undergoing a series of phenotypic changes, CAFs control cancer–stroma interactions through integrin receptor signaling. Here, we isolated CAFs from patients with non‐small‐cell lung cancer (NSCLC) and examined their gene expression profiles. We identified collagen type XI α1 (COL11A1), integrin α11 (ITGA11), and the ITGA11 major ligand collagen type I α1 (COL1A1) among the 390 genes that were significantly enriched in NSCLC‐associated CAFs. Increased ITGA11 expression in cancer stroma was correlated with a poor clinical outcome in patients with NSCLC. Increased expression of fibronectin and collagen type I induced ITGA11 expression in CAFs. The cellular migration of CAFs toward collagen type I and fibronectin was promoted via ERK1/2 signaling, independently of the fibronectin receptor integrin α5β1. Additionally, ERK1/2 signaling induced ITGA11 and COL11A1 expression in cancer stroma. We, therefore, propose that targeting ITGA11 and COL11A1 expressing CAFs to block cancer–stroma interactions may serve as a novel, promising anti‐tumor strategy.