Functional and Clinical Proteomic Exploration of Pancreatic Cancer.

Pancreatic cancer, in most cases being pancreatic ductal adenocarcinoma (PDAC), is one of the most lethal cancers with a median survival time of less than 6 months. Therapeutic options are very limited for patients with PDAC, and surgery is still the most effective treatment, making improvements in early diagnosis critical. One typical characteristic of PDAC is the desmoplastic reaction of its stroma microenvironment, which actively interacts with cancer cells to orchestrate key components in tumorigenesis, metastasis, and chemoresistance. A global exploration of cancer-stroma crosstalk is essential to decipher PDAC biology and design intervention strategies. Over the past decade, the dramatic improvement in proteomics technologies has enabled the profiling of proteins, post-translational modifications (PTMs), and their protein complexes at unprecedented sensitivity and dimensionality. Here, starting with our current understanding of PDAC characteristics, including precursor lesions, progression models, tumor microenvironment, and therapeutic advancements, we describe how proteomics contributes to the functional and clinical exploration of PDAC, providing insights into PDAC carcinogenesis, progression, and chemoresistance. We summarize recent achievements enabled by proteomics to systematically investigate PTMs-mediated intracellular signaling in PDAC, cancer-stroma interactions, and potential therapeutic targets revealed by these functional studies. We also highlight proteomic profiling of clinical tissue and plasma samples to discover and verify useful biomarkers that can aid early detection and molecular classification of patients. In addition, we introduce spatial proteomic technology and its applications in PDAC for deconvolving tumor heterogeneity. Finally, we discuss future prospects of applying new proteomic technologies in comprehensively understanding PDAC heterogeneity and intercellular signaling networks. Importantly, we expect advances in clinical functional proteomics for exploring mechanisms of cancer biology directly by high-sensitivity functional proteomic approaches starting from clinical samples.

A novel histopathological feature of spatial tumor-stroma distribution predicts lung squamous cell carcinoma prognosis.

We used a mathematical approach to investigate the quantitative spatial profile of cancer cells and stroma in lung squamous cell carcinoma tissues and its clinical relevance. The study enrolled 132 patients with 3-5 cm peripheral lung squamous cell carcinoma, resected at the National Cancer Center Hospital East. We utilized machine learning to segment cancer cells and stroma on cytokeratin AE1/3 immunohistochemistry images. Subsequently, a spatial form of Shannon's entropy was employed to precisely quantify the spatial distribution of cancer cells and stroma. This quantification index was defined as the spatial tumor-stroma distribution index (STSDI). The patients were classified as STSDI-low and -high groups for clinicopathological comparison. The STSDI showed no significant association with baseline clinicopathological features, including sex, age, pathological stage, and lymphovascular invasion. However, the STSDI-low group had significantly shorter recurrence-free survival (5-years RFS: 49.5% vs. 76.2%, p < 0.001) and disease-specific survival (5-years DSS: 53.6% vs. 81.5%, p < 0.001) than the STSDI-high group. In contrast, the application of Shannon's entropy without spatial consideration showed no correlation with patient outcomes. Moreover, low STSDI was an independent unfavorable predictor of tumor recurrence and disease-specific death (RFS; HR = 2.668, p < 0.005; DSS; HR = 3.057, p < 0.005), alongside the pathological stage. Further analysis showed a correlation between low STSDI and destructive growth patterns of cancer cells within tumors, potentially explaining the aggressive nature of STSDI-low tumors. In this study, we presented a novel approach for histological analysis of cancer tissues that revealed the prognostic significance of spatial tumor-stroma distribution in lung squamous cell carcinoma.

Autoimmunity, cancer and COVID-19 abnormally activate wound healing pathways: critical role of inflammation.

Recent evidence indicates that targeting IL-6 provides broad therapeutic approaches to several diseases. In patients with cancer, autoimmune diseases, severe respiratory infections [e.g. coronavirus disease 2019 (COVID-19)] and wound healing, IL-6 plays a critical role in modulating the systemic and local microenvironment. Elevated serum levels of IL-6 interfere with the systemic immune response and are associated with disease progression and prognosis. As already noted, monoclonal antibodies blocking either IL-6 or binding of IL-6 to receptors have been used/tested successfully in the treatment of rheumatoid arthritis, many cancer types, and COVID-19. Therefore, in the present review, we compare the impact of IL-6 and anti-IL-6 therapy to demonstrate common (pathological) features of the studied diseases such as formation of granulation tissue with the presence of myofibroblasts and deposition of new extracellular matrix. We also discuss abnormal activation of other wound-healing-related pathways that have been implicated in autoimmune disorders, cancer or COVID-19.

Radionuclide imaging and therapy directed towards the tumor microenvironment: a multi-cancer approach for personalized medicine.

Targeted radionuclide theranostics is becoming more and more prominent in clinical oncology. Currently, most nuclear medicine compounds researched for cancer theranostics are directed towards targets expressed in only a small subset of cancer types, limiting clinical applicability. The identification of cancer-specific targets that are (more) universally expressed will allow more cancer patients to benefit from these personalized nuclear medicine-based interventions. A tumor is not merely a collection of cancer cells, it also comprises supporting stromal cells embedded in an altered extracellular matrix (ECM), together forming the tumor microenvironment (TME). Since the TME is less genetically unstable than cancer cells, and TME phenotypes can be shared between cancer types, it offers targets that are more universally expressed. The TME is characterized by the presence of altered processes such as hypoxia, acidity, and increased metabolism. Next to the ECM, the TME consists of cancer-associated fibroblasts (CAFs), macrophages, endothelial cells forming the neo-vasculature, immune cells, and cancer-associated adipocytes (CAAs). Radioligands directed at the altered processes, the ECM, and the cellular components of the TME have been developed and evaluated in preclinical and clinical studies for targeted radionuclide imaging and/or therapy. In this review, we provide an overview of the TME targets and their corresponding radioligands. In addition, we discuss what developments are needed to further explore the TME as a target for radionuclide theranostics, with the hopes of stimulating the development of novel TME radioligands with multi-cancer, or in some cases even pan-cancer, application.

Safety and efficacy of MIKE-1 in patients with advanced pancreatic cancer: a study protocol for an open-label phase I/II investigator-initiated clinical trial based on a drug repositioning approach that reprograms the tumour stroma.

BACKGROUND: Cancer-associated fibroblasts (CAFs) are an important component of the tumour microenvironment. Recent studies revealed CAFs are heterogeneous and CAF subset(s) that suppress cancer progression (cancer-restraining CAFs [rCAFs]) must exist in addition to well-characterised cancer-promoting CAFs (pCAFs). However, the identity and specific markers of rCAFs are not yet reported. We recently identified Meflin as a specific marker of rCAFs in pancreatic and colon cancers. Our studies revealed that rCAFs may represent proliferating resident fibroblasts. Interestingly, a lineage tracing experiment showed Meflin-positive rCAFs differentiate into α-smooth muscle actin-positive and Meflin-negative CAFs, which are generally hypothesised as pCAFs, during cancer progression. Using a pharmacological approach, we identified AM80, a synthetic unnatural retinoid, as a reagent that effectively converts Meflin-negative pCAFs to Meflin-positive rCAFs. We aimed to investigate the efficacy of a combination of AM80 and gemcitabine (GEM) and nab-paclitaxel (nab-PTX) in patients with advanced pancreatic cancer. METHODS: The phase I part is a 3 + 3 design, open-label, and dose-finding study. The dose-limiting toxicity (DLT) of these combination therapies would be evaluated for 4 weeks. After the DLT evaluation period, if no disease progression is noted based on the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 or if the patient has no intolerable toxicity, administration of AM80 with GEM and nab-PTX would be continued for up to 24 weeks. The phase II part is an open-label, single-arm study. The maximum tolerated dose (MTD) of AM80 with GEM and nab-PTX, determined in phase I, would be administered until intolerable toxicity or disease progression occurs, up to a maximum of 24 weeks, to confirm efficacy and safety. The primary endpoints are frequency of DLT and MTD of AM80 with GEM and nab-PTX in the phase I part and response rate based on the RECIST in the phase II part. Given the historical control data, we hope that the response rate will be over 23% in phase II. DISCUSSION: Strategies to convert pCAFs into rCAFs have been developed in recent years. We hypothesised that AM80 would be a promising enhancer of chemosensitivity and drug distribution through CAF conversion in the stroma. TRIAL REGISTRATION: Clinicaltrial.gov: NCT05064618 , registered on 1 October 2021. jRCT: jRCT2041210056 , registered on 27 August 2021.

Stromal Factors as a Target for Immunotherapy in Melanoma and Non-Melanoma Skin Cancers.

Immune checkpoint inhibitors (ICIs), such as anti-programmed cell death 1 (PD1) antibodies (Abs) and anti-cytotoxic T-lymphocyte associated protein 4 (CTLA4) Abs, have been widely administered for not only advanced melanoma, but also various non-melanoma skin cancers. Since profiles of tumor-infiltrating leukocytes (TILs) play important roles in immunotherapy using ICIs, it is important to evaluate cancer stromal cells such as tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs), as well as stromal extracellular matrix protein, to predict the efficacy of ICIs. This review article focuses particularly on TAMs and related factors. Among TILs, TAMs and their related factors could be the optimal biomarkers for immunotherapy such as anti-PD1 Ab therapy. According to the studies presented, TAM-targeting therapies for advanced melanoma and non-melanoma skin cancer will develop in the future.

Barriers to antibody therapy in solid tumors, and their solutions.

Antibody drugs have become the mainstream of cancer treatment due to advances in cancer biology and Ab engineering. However, several barriers to Ab therapy have also been identified. These include various mechanisms for Ab drug resistance, such as heterogeneity of antigen expression in tumor cells and reduction in antitumor immunity due to expression diversity, polymorphism of Fc receptors (FcR) in effector cells, and reduced function of effector cells. Countermeasures to each resistance mechanism are being investigated. This review focuses on barriers that impede the delivery of Ab drugs due to features of the solid tumor microenvironment. Unlike hematological malignancies, in which the target tumor cells are in blood vessels, clinical solid tumors contain cancer stroma, which interferes with the delivery of Ab drugs. In addition, the cancer mass itself interferes with the penetration of Ab drugs. In this article, I will consider the etiology of cancer stroma and propose a new Ab drug development strategy for solid cancer treatment centering on cancer stromal targeting (CAST) therapy using anti-insoluble fibrin Ab-drug conjugate (ADC), which can overcome the cancer stroma barrier. The recent success of ADCs, chimeric antigen receptor T cells (CAR-Ts), and Bi-specific Abs is changing the category of Ab drugs from molecular-targeted drugs based on growth signal inhibition to cancer-specific targeted therapies. Therefore, at the end of this review, I argue that it is time to reorient the concept of Ab drug development.

Histological categorisation of the desmoplastic reaction is a predictor of patient prognosis in oesophageal squamous cell carcinoma.

AIMS: Histological categorisation of the desmoplastic reaction (DR) is an independent prognostic factor in colorectal cancer. However, it is unknown whether DR categorisation is predictive of oesophageal squamous cell carcinoma (OSCC) outcomes. This study aimed to evaluate the prognostic value of DR categorisation in OSCC patients. METHODS AND RESULTS: Data were collected from 118 patients with OSCC who underwent a curative oesophagectomy with T2 or deeper wall invasion. The DR in each tumour was classified as mature, intermediate or immature based on the presence or absence of keloid-like collagen and myxoid stroma. We identified 49 mature DR tumours, 41 intermediate DR tumours and 28 immature DR tumours. The 5-year overall survival (OS) rate was highest in the mature DR group (42.8%), followed by the intermediate DR group (25.0%) and the immature DR group (19.9%) (P = 0.022, log-rank test; P = 0.006, log-rank trend test). The 5-year disease-specific survival (DSS) rate was also highest in the mature DR group (48.5%), followed by the intermediate DR group (30.8%) and the immature DR group (26.8%) (P = 0.031, log-rank test; P = 0.010, log-rank trend test, respectively). Multivariate analysis revealed that an immature DR was an independent poor prognostic factor of OS and DSS (P = 0.002 and P = 0.004). CONCLUSIONS: DR categorisation of OSCC stroma following oesophagectomy is a useful diagnostic tool and an independent prognostic marker.

Histopathological atlas of desmoplastic reaction characterization in colorectal cancer.

Emergent scientific evidence indicates the central role of cancer-associated fibroblasts in determining whether the microenvironment of cancer works as friend or foe of the host; however, there is no unified histological evaluation framework of fibrotic stroma in colorectal cancers. Myxoid stroma and keloid-like collagen are site-specific histopathological features generated by cancer-associated fibroblasts, which appear exclusively in the tumor front during desmoplastic reaction. On the basis of these two stromal components, desmoplastic reaction is categorized into three patterns-immature, intermediate and mature-using hematoxylin and eosin staining. In January 2020, a prospective randomized clinical trial, JCOG1805, to elucidate the value of adjuvant chemotherapy in stage II colorectal cancer patients with pathological risk factors of recurrence was launched in Japan, in which intermediate/immature desmoplastic reaction is one of the four risk factors selected as inclusion criteria. This paper covers the diagnostic criteria for the desmoplastic reaction classification being used in the JCOG1805 study.

Targeting the Stromal Pro-Tumoral Hyaluronan-CD44 Pathway in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies. Present-day treatments have not shown real improvements in reducing the high mortality rate and the short survival of the disease. The average survival is less than 5% after 5 years. New innovative treatments are necessary to curtail the situation. The very dense pancreatic cancer stroma is a barrier that impedes the access of chemotherapeutic drugs and at the same time establishes a pro-proliferative symbiosis with the tumor, thus targeting the stroma has been suggested by many authors. No ideal drug or drug combination for this targeting has been found as yet. With this goal in mind, here we have explored a different complementary treatment based on abundant previous publications on repurposed drugs. The cell surface protein CD44 is the main receptor for hyaluronan binding. Many malignant tumors show over-expression/over-activity of both. This is particularly significant in pancreatic cancer. The independent inhibition of hyaluronan-producing cells, hyaluronan synthesis, and/or CD44 expression, has been found to decrease the tumor cell's proliferation, motility, invasion, and metastatic abilities. Targeting the hyaluronan-CD44 pathway seems to have been bypassed by conventional mainstream oncological practice. There are existing drugs that decrease the activity/expression of hyaluronan and CD44: 4-methylumbelliferone and bromelain respectively. Some drugs inhibit hyaluronan-producing cells such as pirfenidone. The association of these three drugs has never been tested either in the laboratory or in the clinical setting. We present a hypothesis, sustained by hard experimental evidence, suggesting that the simultaneous use of these nontoxic drugs can achieve synergistic or added effects in reducing invasion and metastatic potential, in PDAC. A non-toxic, low-cost scheme for inhibiting this pathway may offer an additional weapon for treating pancreatic cancer.

Upregulation of adipocyte enhancer-binding protein 1 in endothelial cells promotes tumor angiogenesis in colorectal cancer.

Tumor angiogenesis is an important therapeutic target in colorectal cancer (CRC). We aimed to identify novel genes associated with angiogenesis in CRC. Using RNA sequencing analysis in normal and tumor endothelial cells (TECs) isolated from primary CRC tissues, we detected frequent upregulation of adipocyte enhancer-binding protein 1 (AEBP1) in TECs. Immunohistochemical analysis revealed that AEBP1 is upregulated in TECs and stromal cells in CRC tissues. Quantitative RT-PCR analysis showed that there is little or no AEBP1 expression in CRC cell lines, but that AEBP1 is well expressed in vascular endothelial cells. Levels of AEBP1 expression in Human umbilical vein endothelial cells (HUVECs) were upregulated by tumor conditioned medium derived from CRC cells or by direct coculture with CRC cells. Knockdown of AEBP1 suppressed proliferation, migration, and in vitro tube formation by HUVECs. In xenograft experiments, AEBP1 knockdown suppressed tumorigenesis and microvessel formation. Depletion of AEBP1 in HUVECs downregulated a series of genes associated with angiogenesis or endothelial function, including aquaporin 1 (AQP1) and periostin (POSTN), suggesting that AEBP1 might promote angiogenesis through regulation of those genes. These results suggest that upregulation of AEBP1 contributes to tumor angiogenesis in CRC, which makes AEBP1 a potentially useful therapeutic target.

The Axin2-snail axis promotes bone invasion by activating cancer-associated fibroblasts in oral squamous cell carcinoma.

BACKGROUND: In bone-invasive oral squamous cell carcinoma (OSCC), cancer-associated fibroblasts (CAFs) infiltrate into bony tissue ahead of OSCC cells. In the present study, we aimed to investigate the role of the Axin2-Snail axis in the biological behaviour of CAFs and bone invasion in OSCC. METHODS: The clinicopathological significance of Axin2 and Snail expression was investigated by immunohistochemistry in an OSCC cohort containing 217 tissue samples from patients with long-term follow-up. The influence of the Axin2-Snail axis on the biological behaviour of OSCC cells and CAFs was further investigated both in vitro and in vivo. RESULTS: Axin2 expression was significantly associated with Snail expression, the desmoplasia status, and bone invasion in patients with OSCC. In multivariate analysis, lymph node metastasis, desmoplasia, Axin2 expression, and Snail expression were independent poor prognostic factors in our cohort. Consistent with these findings, OSCC cells demonstrated attenuated oncogenic activity as well as decreased expression of Snail and various cytokines after Axin2 knockdown in vitro. Among the related cytokines, C-C motif chemokine ligand 5 (CCL5) and interleukin 8 (IL8) demonstrated a strong influence on the biological behaviour of CAFs in vitro. Moreover, both the desmoplastic reaction and osteolytic lesions in the calvaria were predominantly decreased after Axin2 knockdown in OSCC cells in vivo using a BALB/c athymic nude mouse xenograft model. CONCLUSIONS: Oncogenic activities of the Axin2-Snail axis are not limited to the cancer cells themselves but rather extend to CAFs via regulation of the cytokine-mediated cancer-stromal interaction, with further implications for bone invasion as well as a poor prognosis in OSCC.

Fibroblasts in the Tumor Microenvironment.

The implications of a tumor microenvironment in cancer initiation and progression have drawn interest in recent years. Within the tumor stroma, fibroblasts represent a predominant cell type and are responsible for the majority of extracellular components within the tumor microenvironment, such as matrix and soluble factors. A switch from quiescent fibroblasts to cancer-associated fibroblasts triggers a large variety of pro-tumorigenic signals that support tumor progression and shape the surrounding pathological stroma, with the remodeling of tissue architecture and repression of the local immune response. The heterogeneous nature of cancer-associated fibroblasts and their multiple functions are subject of active research as they could represent promising targets for cutting-edge therapeutic approaches to cancer and the tumor microenvironment.

Overexpression of matriptase in tumor stroma is a poor prognostic indicator of extrahepatic bile duct cancer.

Bile duct cancer is known to contain numerous fibroblasts, and reported to recruit cancer- associated fibroblasts by secreting platelet-derived growth factor-D (PDGF-D) which needs serine proteases, such as matriptase, to behave as a ligand. However, their expression pattern, and prognostic value have not been clarified. In this study, we investigated the clinicopathological significance of PDGF-D and matriptase expression in patients with extrahepatic bile duct cancer. The samples were obtained from 256 patients who underwent the surgical resection between 1991 and 2015, and the expression levels of PDGF-D and matriptase were evaluated immunohistochemically. Staining intensities and distribution were scored, and finally classified into low and high expression groups in cancer cells and stroma respectively. High expression of matriptase in the cancer stroma was detected in 91 tumors (40%). The high stromal matriptase expression was significantly associated with shorter recurrence-free survival (RFS) and overall survival (OS) (P = 0.0027 and 0.0023, respectively). Multivariate analyses also demonstrated that the stromal matriptase expression level was an independent influential factor in RFS (P = 0.0050) and OS (P = 0.0093). Our findings suggest that the high stromal matriptase expression was strongly associated with tumor progression, recurrence and poor outcomes in patients with extrahepatic bile duct cancer.

Tumor-stromal cross-talk modulating the therapeutic response in pancreatic cancer.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant solid tumor with a dismal prognosis. The stroma component makes up to 90% of the tumor mass and is thought to be one of the main reasons for the tumor's high chemoresistance. Cancer associated fibroblasts (CAFs) have previously been identified to be the key stromal players. This is the first time we provide detailed in vitro experiments investigating tumor-stromal interactions when exposed to three well-known chemotherapeutic agents. METHODS: Monocultures, indirect and direct co-cultures of two PDAC cell lines (AsPC and Panc-1) and six primary patients derived CAFs were treated with gemcitabine, nab-paclitaxel and the γ-secretase-inhibitor (GSI) DAPT. The cell viability of each component was measured with XTT. Finally, IL-6 concentrations of the supernatants were analyzed. RESULTS: On the contrary to PDAC cell lines, CAF monocultures hardly responded to any treatment which suggested that stroma (CAFs) itself is more resistant to standard chemo-treatments than the epithelial cancer cells. Moreover, only a weak chemotherapeutic response was observed in direct co-cultures of cancer cells with CAFs. A change in the morphology of direct co-cultures was accompanied with the chemoresistance. CAFs were observed to build cage-like structures around agglomerates of tumor cells. High levels of IL-6 were also associated with a reduced response to therapy. Indirect co-cultures make the tumor-stromal interaction more complex. CONCLUSIONS: CAFs are highly chemoresistant. Direct cell-cell contact and high levels of IL-6 correlate with a high chemoresistance.

Discoidin domain receptor 1 activity drives an aggressive phenotype in gastric carcinoma.

BACKGROUND: Discoidin domain receptor 1 (DDR1), a receptor tyrosine kinase that utilizes collagen as a ligand, is a key molecule in the progression of solid tumors as it regulates the interaction of cancer cells with the tumor stroma. However, the clinical relevance of DDR1 expression in gastric carcinoma is yet to be investigated. Here, we assessed the role of DDR1 in mediating the aggressive phenotype of gastric carcinoma and its potential as a therapeutic target. METHODS: We conducted DDR1 immunohistochemistry using a tissue microarray of 202 gastric carcinoma specimens. We examined the effect of collagen-induced activation of DDR1 on cell signaling, tumorigenesis, and cell migration in gastric cancer cell lines, and tumor growth in a xenograft animal model of gastric cancer. RESULTS: Our results showed that 50.5% of gastric cancer tissues are positive for DDR1 expression, and positive DDR1 expression was significantly correlated with a poor prognosis (P = 0.015). In a subgroup analysis, DDR1 expression was prognostically meaningful only in patients receiving adjuvant treatment (P = 0.013). We also demonstrated that collagen was able to activate DDR1 and increase the clonogenicity and migration of gastric cancer cells. We observed that a DDR1 inhibitor, 7rh benzamide, suppressed tumor growth in gastric cancer xenografts. CONCLUSIONS: Our findings suggest a key role for DDR1 signaling in mediating the aggressive phenotype of gastric carcinoma. Importantly, inhibition of DDR1 is an attractive strategy for gastric carcinoma therapy.

Fatty Acids Induce Stemness in the Stromal Cells of a CT26 Mouse Tumor Model.

The potential effects of 2 types of fatty acids on colorectal cancer (CRC) were assessed using cancer stromal cells. Linoleic acid (LA; C-18, n-6 unsaturated fatty acid) and elaidic acid (EA; C-18, trans acid), both known to affect colon carcinogenesis and cancer progression, were administered by gavage to BALB/c mice, which were inoculated with CT26 syngeneic colon cancer cells in the back. Both EA and LA treatments enhanced tumor growth and metastasis. EA and LA also increased the number of CD133-positive stromal cells in the tumor capsule. Importantly, those cancer cells at the tumor periphery, physically attached to CD133-positive stromal cells, also expressed CD133. These findings suggest that EA and LA might induce stemness in cancer cells through physical association and promote cancer metastasis.

The myofibroblast, a key cell in normal and pathological tissue repair.

Myofibroblasts are characterized by their expression of α-smooth muscle actin, their enhanced contractility when compared to normal fibroblasts and their increased synthetic activity of extracellular matrix proteins. Myofibroblasts play an important role in normal tissue repair processes, particularly in the skin where they were first described. During normal tissue repair, they appear transiently and are then lost via apoptosis. However, the chronic presence and continued activity of myofibroblasts characterize many fibrotic pathologies, in the skin and internal organs including the liver, kidney and lung. More recently, it has become clear that myofibroblasts also play a role in many types of cancer as stromal or cancer-associated myofibroblast. The fact that myofibroblasts are now known to be key players in many pathologies makes understanding their functions, origin and the regulation of their differentiation important to enable them to be regulated in normal physiology and targeted in fibrosis, scarring and cancer.

MicroRNA in Metabolic Re-Programming and Their Role in Tumorigenesis.

The process of metabolic re-programing is linked to the activation of oncogenes and/or suppression of tumour suppressor genes, which are regulated by microRNAs (miRNAs). The interplay between oncogenic transformation-driven metabolic re-programming and modulation of aberrant miRNAs further established their critical role in the initiation, promotion and progression of cancer by creating a tumorigenesis-prone microenvironment, thus orchestrating processes of evasion to apoptosis, angiogenesis and invasion/migration, as well metastasis. Given the involvement of miRNAs in tumour development and their global deregulation, they may be perceived as biomarkers in cancer of therapeutic relevance.

Stromal miR-21 is more important than miR-21 of tumour cells for the progression of gastric cancer.

BACKGROUND: Gastric cancer (GC) is a common cancer globally. miRNA-21 (miR-21) appears to be important in the tumourigenesis of almost all types of human cancer. However its precise localization in GC has yet to be clarified. We thus examined miR-21 localization in GC and revealed its clinicopathological importance. METHODS: Tissue arrays of 469 GCs from 454 patients were examined for miR-21 using in situ hybridization (ISH). The positivity was evaluated separately in tumour cells and stromal cells. Conventional sections of 10 GCs were also stained. Eight cases were examined by quantitative RT-PCR (qRT-PCR). RESULTS: miR-21 was highly expressed in tumour cells of 44% of cases and in cancer stroma of 51% of cases. miR-21 of tumour cells was not related to clinicopathological factors, whereas stromal miR-21 was related to many factors including tumour stage, size, and nodal metastasis. Stromal miR-21 gradually increased during tumour progression. ISH of whole sections showed stronger stromal positivity in invasive areas with desmoplastic reaction. Cancer stroma also showed higher miR-21 expression than tumour and non-tumourous tissue in the qRT-PCR study. CONCLUSION: Stromal miR-21 is closely related to tumour progression in GC. Stromal miR-21 of tumours might be a target of treatment.