Facilitate Tumor Cell Migration Research Articles

Convolutional Neural Network Approach for White Blood Cells Classification

White blood cells (WBCs) or leukocytes are immune cells responsible for protecting the body against infections, engulfing foreign invaders, repairing tissue injuries, and resisting pathogens or diseases. WBCs such as macrophages, neutrophils, T cells, and natural killer cells (NK cells) are essential players in many important diseases. For example, in cancer, WBCs remodel the tumor extracellular matrix, facilitate tumor cell migration and invasion, and modulate tumor angiogenesis. Through these activities, WBCs promote all stages of tumor progression. The system is developed the DL algorithms such as convolutional neural network for predicting the types of blood cell disease. Finally, the system can estimate some performance metrics such as accuracy and error rate. Keywords—Image Segmentation, White blood cells, Convolutional Neural Network, Deep learning, Blood leukocytes segmentation.

Cancer-associated mesenchymal stem/stromal cells: role in progression and potential targets for therapeutic approaches.

Malignancies contain a relatively small number of Mesenchymal stem/stromal cells (MSCs), constituting a crucial tumor microenvironment (TME) component. These cells comprise approximately 0.01-5% of the total TME cell population. MSC differentiation potential and their interaction with the tumor environment enable these cells to affect tumor cells' growth, immune evasion, metastasis, drug resistance, and angiogenesis. This type of MSC, known as cancer-associated mesenchymal stem/stromal cells (CA-MSCs (interacts with tumor/non-tumor cells in the TME and affects their function by producing cytokines, chemokines, and various growth factors to facilitate tumor cell migration, survival, proliferation, and tumor progression. Considering that the effect of different cells on each other in the TME is a multi-faceted relationship, it is essential to discover the role of these relationships for targeting in tumor therapy. Due to the immunomodulatory role and the tissue repair characteristic of MSCs, these cells can help tumor growth from different aspects. CA-MSCs indirectly suppress antitumor immune response through several mechanisms, including decreasing dendritic cells (DCs) antigen presentation potential, disrupting natural killer (NK) cell differentiation, inducing immunoinhibitory subsets like tumor-associated macrophages (TAMs) and Treg cells, and immune checkpoint expression to reduce effector T cell antitumor responses. Therefore, if these cells can be targeted for treatment so that their population decreases, we can hope for the treatment and improvement of the tumor conditions. Also, various studies show that CA-MSCs in the TME can affect other vital aspects of a tumor, including cell proliferation, drug resistance, angiogenesis, and tumor cell invasion and metastasis. In this review article, we will discuss in detail some of the mechanisms by which CA-MSCs suppress the innate and adaptive immune systems and other mechanisms related to tumor progression.

Lactic acid-induced M2-like macrophages facilitate tumor cell migration and invasion via the GPNMB/CD44 axis in oral squamous cell carcinoma

Oral squamous cell carcinoma (OSCC) is the most prevalent form of oral and maxillofacial malignancies, characterized by a low five-year survival rate primarily caused by invasion and metastasis. The progression of OSCC is influenced by macrophage-mediated immunosuppression, which contributes to both local invasion and distant metastasis. Herein, it is of great necessity to explore the molecular mechanisms underlying the crosstalk between OSCC cells and macrophages, as it remains unclear. In the present study, we found that lactic acid orchestrated intracellular communication in the tumor microenvironment. Glycoprotein non-metastatic protein B (GPNMB), a remarkable molecule preferentially expressed by tumor-associated macrophages (TAMs), was significantly highly expressed in the OSCC tissue. The results showed that lactic acid induced macrophage polarization towards an M2-like phenotype and orchestrated GPNMB secretion from macrophages. Furthermore, paracrine GPNMB played a critical role in triggering tumor-promoting activities such as facilitating tumor cell migration, invasion, and epithelial–mesenchymal transition (EMT). In terms of molecular mechanism, GPNMB functionally interacted with the CD44 receptor, and then partially activated the PI3K/AKT/mTOR signaling cascade. Silencing of CD44 could attenuate the tumor-promoting effects of GPNMB in OSCC cells. Collectively, our findings decipher a positive feedback loop in which tumor cells metabolically interact with macrophages in the OSCC microenvironment, highlighting the potential for therapeutic targeting of the GPNMB/CD44 axis as a promising strategy for treating OSCC.

Abstract 3930: MCT1 as a potential target in the progression of oral premalignant dysplasia to invasive squamous cell carcinoma

Abstract Introduction: Most oral squamous cell carcinomas (OSCC) progress through clinically identifiable stages, starting from premalignant epithelial dysplasia to early invasive OSCC. How cells transform from premalignant dysplasia to early invasive OSCC is unknown. High monocarboxylate transporter 1 (MCT1; SLC16A1) expression is correlated with poor outcomes in OSCC patients, where it is thought to promote tumor growth by supporting metabolic coupling between cancer cells and tumor stroma. Because expression of MCT1 is markedly increased in OSCC patients, we sought to determine if MCT1 played a role in the progression of oral dysplasia in early invasive OSCC. Methods: Immunohistochemistry (IHC) was used to evaluate changes in the levels of MCT1 expression across adjacent normal, dysplasia, and OSCC tissues to identify expression patterns during cancer progression. Genetic knockout (KO) of SLC16A1 via CRISPR/Cas9 and pharmacological blockade by the MCT1 inhibitor AZD3965 were used on OSCC (TR146) and dysplastic (DOK) cell lines. KO was confirmed by qRT-PCR and immunoblotting. MCT1-KO and AZD3965-treated cells were assayed for changes in cell invasion using Matrigel-coated transwell assays. Correlative changes in gene expression based on MCT1 staining and disease progression were also observed in adjacent normal, dysplasia, and OSCC regions in each tissue section using Nanostring GeoMx Digital Spatial Profiler. Results: Expression of MCT1 was directly correlated to the progression of disease from dysplasia to early superficially invasive OSCC relative to normal adjacent epithelium. KO of MCT1 significantly decreased the invasion of dysplastic and OSCC cell lines compared to the wild-type (parental) controls. AZD3965 also decreased invasion in the parental dysplastic and OSCC lines. To identify progressive changes in gene expression across normal, dysplasia, and early invasive OSCC, transcripts for cancer-related genes were quantified in the epithelial and stromal compartments from patient samples. Compared to the normal epithelium, upregulation in gene expression, including SLC16A1, was observed in the cell cycle and metabolic pathways in OSCC tissues. Conclusions: Our data suggest that MCT1 plays a key role in breaching of the basement membrane and facilitating tumor cell migration and invasion. Targeting MCT1 in oral dysplasia may prevent progression to OSCC in oral cancer patients. Citation Format: Ethan J. Wong, Ali Khammanivong, Ravi Maisuria, Erin B. Dickerson, Raj Gopalakrishnan. MCT1 as a potential target in the progression of oral premalignant dysplasia to invasive squamous cell carcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3930.

Abstract 831: Discovery of a novel soluble Neuropilin-2 isoform with antiangiogenic and antitumorigenic activity

Abstract Upregulation of the non-tyrosine kinase receptor neuropilin-2 (NRP2) is described for several tumor entities and correlates with disease progression. Two membrane-anchored isoforms are transcribed from the NRP2 gene that only differ in their terminal exons to encode transmembrane stretches and short cytoplasmic tails, respectively. While NRP2a was shown to support tumor cell proliferation, NRP2b facilitates tumor cell migration, resulting in enhanced metastatic spreading. A third, soluble NRP2 isoform encoding only aminoterminal protein domains exists as dimeric protein and functions in sequestration of the VEGF-C ligand. By using a next-generation sequencing approach to enrich for NRP2 terminal exons, we identified NRP2-Mo83, a novel NRP2 isoform, from a high expressing tumor cell line, and verified secreted NRP2-Mo83 protein by mass spectrometry in cell supernatants. Preliminary mass spectrometric data give an indication of the presence of soluble NRP2-Mo83 protein in human serum samples.NRP2-Mo83 mRNA is expressed at variable quantities in vitro in a panel of bladder carcinoma cell lines, but is downregulated in a small cohort of macrodissected urothelial carcinoma samples. Transcript abundances of a NRP2 transcript classified as non-coding with high sequence similarity to the NRP2-Mo83 3’ terminus confirm the observed downregulation in the TCGA bladder carcinoma cohort.Preliminary data indicate that recombinant NRP2-Mo83 protein exerts a dose-dependent inhibitory effect on tumor cell growth in vitro in all tested bladder carcinoma cell lines in the presence of serum. However, a fraction of cell lines does not respond to NRP2-Mo83 under serum-starved conditions. Proliferation of human endothelial cells (HUVEC) is inhibited in a dose-dependent manner by recombinant NRP2-Mo83 protein in vitro. In vivo, NRP2-Mo83 reveals an anti-angiogenic effect on the chicken chorioallantoic membrane.Recombinant NRP2-Mo83 is secreted by HEK293 cells. Enrichment of endogenous and purification of recombinant NRP2-Mo83 protein is achieved by exploiting its capacity to bind heparin. In contrast to the described s9NRP2 isoform, NRP2-Mo83 is largely monomeric in solution, as verified by size exclusion chromatography. We identified N and O glycosylation as well as the capacity for polysialation as posttranslational modifications of recombinant NRP2-Mo83 protein, similar to membrane anchored NRP2 isoforms. NanoDSF experiments indicate that calcium ions stabilize NRP2-Mo83. We present NRP2-Mo83 as a novel NRP2 splice isoform, validated its expression at the mRNA and protein level. NRP2-Mo83 appears down-regulated during bladder tumorigenesis, congruent with its function in bladder tumor growth inhibition and its anti-angiogenic properties in vitro and in vivo. The identification of NRP2-Mo83 in human serum may suggest a suppressive function even under non-pathological conditions. Citation Format: Thomas Mayr, Paul L. Dix, Sayed-Mohammad Hasheminasab, Chuanpit Hampel, Marc Sylvester, Niels Schneberger, Sarah Foerster, Gregor Hagelueken, Samikshan Dutta, Glen Kristiansen, Regine Schneider-Stock, Kaustubh Datta, Michael H. Muders. Discovery of a novel soluble Neuropilin-2 isoform with antiangiogenic and antitumorigenic activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 831.

Role of macrophages in tumor progression and therapy (Review).

The number and phenotype of macrophages are closely related to tumor growth and prognosis. Macrophages are recruited to (and polarized at) the tumor site thereby promoting tumor growth, stimulating tumor angiogenesis, facilitating tumor cell migration, and creating a favorable environment for subsequent colonization by (and survival of) tumor cells. These phenomena contribute to the formation of an immunosuppressive tumor microenvironment (TME) and therefore speed up tumor cell proliferation and metastasis and reduce the efficacy of antitumor factors and therapies. The ability of macrophages to remodel the TME through interactions with other cells and corresponding changes in their number, activity, and phenotype during conventional therapies, as well as the association between these changes and drug resistance, make tumor-associated macrophages a new target for antitumor therapies. In this review, advantages and limitations of the existing antitumor strategies targeting macrophages in Traditional Chinese and Western medicine were analyzed, starting with the effect of macrophages on tumors and their interactions with other cells and then the role of macrophages in conventional treatments was explored. Possible directions of future developments in this field from an all-around multitarget standpoint were also examined.

Role of interstitial flow in tumor migration through 3D ECM

Cancer invasion in tissue is simultaneously regulated by chemical and mechanical cues. Evidences suggest that interstitial flow plays a critical role in tumor metastasis. On one hand, the distribution of chemokines around cell is influenced by flow. On the other hand, interstitial flow may reconfigure the alignment of fiber matrix, which greatly changes the contact force between cell and extracellular matrix. In this study, we have upgraded a model by which we can quantitatively investigate the influence of flow on tumor cell migration. A hydrodynamic analysis of shear stress on a slender body is introduced to simulate the fiber realignment. Factors such as subtle flow and cell–matrix interaction which dominate tumor migration are integrated in this novel model. Simulation results show interstitial flow facilitates tumor cell migration in the flow direction. Moreover, the flow-related chemical and mechanical cues have a synergistic effect on the migration. This model provides better understanding on cancer metastasis and helps design vitro experiment precisely.

Obesity-associated Adipose Stromal Cells Promote Breast Cancer Invasion Through Direct Cell Contact and ECM Remodeling.

Obesity increases the risk and worsens the prognosis for breast cancer due, in part, to altered adipose stromal cell (ASC) behavior. Whether ASCs from obese individuals increase migration of breast cancer cells relative to their lean counterparts, however, remains unclear. To test this connection, multicellular spheroids composed of MCF10A-derived tumor cell lines of varying malignant potential and lean or obese ASCs were embedded into collagen scaffolds mimicking the elastic moduli of interstitial breast adipose tissue. Confocal image analysis suggests that tumor cells alone migrate insignificantly under these conditions. However, direct cell-cell contact with either lean or obese ASCs enables them to migrate collectively, whereby obese ASCs activate tumor cell migration more effectively than their lean counterparts. Time-resolved optical coherence tomography (OCT) imaging suggests that obese ASCs facilitate tumor cell migration by mediating contraction of local collagen fibers. Matrix metalloproteinase (MMP)-dependent proteolytic activity significantly contributes to ASC-mediated tumor cell invasion and collagen deformation. However, ASC contractility is also important, as co-inhibition of both MMPs and contractility is necessary to completely abrogate ASC-mediated tumor cell migration. These findings imply that obesity-mediated changes of ASC phenotype may impact tumor cell migration and invasion with potential implications for breast cancer malignancy in obese patients.

Matrix Metalloproteinases' Role in Tumor Microenvironment.

Cancer cells evolve in the tumor microenvironment (TME) by the acquisition of characteristics that allow them to initiate their passage through a series of events that constitute the metastatic cascade. For this purpose, tumor cells maintain a crosstalk with TME non-neoplastic cells transforming them into their allies. "Corrupted" cells such as cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), and tumor-associated neutrophils (TANs) as well as neoplastic cells express and secrete matrix metalloproteinases (MMPs). Moreover, TME metabolic conditions such as hypoxia and acidification induce MMPs' synthesis in both cancer and stromal cells. MMPs' participation in TME consists in promoting events, for example, epithelial-mesenchymal transition (EMT), apoptosis resistance, angiogenesis, and lymphangiogenesis. MMPs also facilitate tumor cell migration through the basement membrane (BM) and extracellular matrix (ECM). The aim of the present chapter is to discuss MMPs' contribution to the evolution of cancer cells, their cellular origin, and their influence in the main processes that take place in the TME.

Fibroblast-Derived 3D Matrix System Applicable to Endothelial Tube Formation Assay.

The extracellular matrix (ECM) is a three-dimensional scaffold that acts as the main support for cells in tissues. Besides its structural function, the ECM also participates in cell migration, proliferation, and differentiation. Fibroblasts are the main type of cells modifying ECM fiber arrangement and production. In cancer, CAFs (cancer associated fibroblasts) are in permanent activation status, participating in ECM remodeling, facilitating tumor cell migration, and stimulating tumor-associated angiogenesis, among other pro-tumorigenic roles. The objective of this method is to create a three-dimensional matrix with a fiber composition that is similar to in vivo matrices, using immortalized fibroblasts or human primary CAFs. Fibroblasts are cultured in pre-treated cell culture plates and grown under ascorbic acid stimulation. Then, fibroblasts are removed and matrices are blocked for further cell seeding. In this ECM model, fibroblasts can be activated or modified to generate different kinds of matrix, whose effects can be studied in cell culture. 3D matrices are also shaped by cell signals, like degradation or cross-linking enzymes that might modify fiber distribution. In this context, angiogenesis can be studied, along with other cell types such as epithelial tumor cells.

Fbxw7 regulates renal cell carcinoma migration and invasion via suppression of the epithelial-mesenchymal transition.

F-box and WD repeat domain containing 7 (Fbxw7) is an F-box protein that belongs to the SKP1-CUL1-F-box protein E3 ligase complex and is responsible for transferring the ubiquitin molecule to the substrate, which results in its recognition and subsequent degradation by proteasomes. Furthermore, it can identify a network of signaling proteins that function in cell growth, diversion and apoptosis. In the present study, Fbxw7 was downregulated in renal cell carcinoma (RCC) tissues compared with the adjacent non-tumor tissues and its expression was significantly associated with the tumor-node-metastasis stage, lymph node metastasis and distant metastasis in patients with RCC. Furthermore, multivariate Cox regression analyses indicated that Fbxw7 expression was an independent factor for the prediction of the overall survival of patients with RCC. A functional study demonstrated that downregulation of Fbxw7 facilitated tumor cell migration and invasion via the epithelial-mesenchymal transition (EMT). Therefore, the results of the current study indicted that Fbxw7 is an anti-oncogene that serves a notable function in RCC development by suppressing RCC metastasis and the EMT, indicating the potential therapeutic value of Fbxw7 in inhibiting metastasis in RCC.

A Review of Ruthenium Complexes Activities on Breast Cancer Cells.

Cancer is one of the main causes of death worldwide. Breast cancer is the most prevalent type of cancer in women and the leading cause of cancer deaths due to its high metastasis to the lymph nodes, lungs bones and brain. Interactions with the stromal microenvironment surrounding tumor cells facilitate tumor cell migration and invasion of tissues and dissemination to other organs, to form metastasis. The development of antitumor metal-based drugs was originated with the discovery of cisplatin, however, its severe side effects represent a limitation for its clinical use. Ruthenium (Ru) complexes with different ligands have been successfully studied as promising antitumor drugs. In this review, we focused on the effects of Ru complexes on breast cancer cells and their impact on different steps of the metastatic process.

GRP78 plays an integral role in tumor cell inflammation-related migration induced by M2 macrophages

Macrophages are the main immune-competent cells that infiltrate in tumors. Tumor-associated macrophages (TAMs), termed M2 macrophages, facilitate tumor progress and promote metastasis. However, M2 macrophages always display an immunosuppressive phenotype, which is not in accordance with the tumor inflammatory microenvironment and inflammation-related metastasis. In this study, we established a macrophage polarization model with human monocytes and found that the conditioned medium from M2 macrophages increased GRP78 expression in tumor cells and facilitated tumor cell migration. Mechanistically, excessive GRP78 formed a protein complex with STAT3 and JAK2 to promote STAT3 phosphorylation. Furthermore, p-STAT3 facilitated the high expression of inflammatory factors IL-1β and TNF-α in tumor cells, which was important in M2 macrophage-induced metastasis. The present data demonstrate that M2 macrophages elevate tumor cell GRP78 expression to trigger an inflammatory response, which further facilitates tumor metastasis. Therefore, our study not only uncovered a new cause of GRP78 overexpression in tumor cell, but also, explained the antinomy of TAMs immunosuppressive properties and inflammation-related tumor metastasis.

PCAF inhibits hepatocellular carcinoma metastasis by inhibition of epithelial-mesenchymal transition by targeting Gli-1

The p300–CBP-associated factor (PCAF), other than its histone acetyltransferase (HAT) activity, possesses an intrinsic ubiquitination activity that is involved in various transcriptional regulators, including the transcription factor glioma-associated oncogene 1 (Gli1), a well-known regulator of epithelial–mesenchymal transition (EMT) in cancer. In present research, we detected that PCAF was down-regulated in hepatocellular carcinoma (HCC) tissues compared with the adjacent non-tumor tissues and significantly associated with malignant portal vein invasion (p < 0.05) and poor survival (p < 0.05) of HCC patients. Moreover, functional study demonstrated that downregulation of PCAF facilitated tumor cell migration, invasion via EMT. Further study found that Gli1 as a direct target of PCAF induced EMT and promoted tumor metastasis and invasion. Conclusion: PCAF is an anti-oncogene that plays an important role in the development of HCC by suppressing HCC cell metastasis and EMT by targeting Gli1, which indicates the potential therapeutic value of PCAF for suppression of metastasis of HCC.

Protease-activated receptors (PARs)--biology and role in cancer invasion and metastasis.

Although many studies have demonstrated that components of the hemostatic system may be involved in signaling leading to cancer progression, the potential mechanisms by which they contribute to cancer dissemination are not yet precisely understood. Among known coagulant factors, tissue factor (TF) and thrombin play a pivotal role in cancer invasion. They may be generated in the tumor microenvironment independently of blood coagulation and can induce cell signaling through activation of protease-activated receptors (PARs). PARs are transmembrane G-protein-coupled receptors (GPCRs) that are activated by a unique proteolytic mechanism. They play important roles in vascular physiology, neural tube closure, hemostasis, and inflammation. All of these agents (TF, thrombin, PARs—mainly PAR-1 and PAR-2) are thought to promote cancer invasion and metastasis at least in part by facilitating tumor cell migration, angiogenesis, and interactions with host vascular cells, including platelets, fibroblasts, and endothelial cells lining blood vessels. Here, we discuss the role of PARs and their activators in cancer progression, focusing on TF- and thrombin-mediated actions. Therapeutic options tailored specifically to inhibit PAR-induced signaling in cancer patients are presented as well.

Abstract LB-145: Astrocytes directly influence tumor cell invasion and metastasis in vivo

Abstract Brain metastasis is a defining component of tumor pathophysiology, and the underlying mechanisms responsible for this phenomenon are not well understood. Current dogma is that tumor cells stimulate and activate astrocytes, and this mutual relationship is critical for tumor cell sustenance in the brain. Here, we provide evidence that primary rat neonatal and adult astrocytes secrete factors that proactively induced human lung and breast tumor cell invasion and metastasis capabilities. Among which, tumor invasion factors namely matrix metalloprotease-2 (MMP-2) and MMP-9 were partly responsible for the astrocyte media-induced tumor cell invasion. Inhibiting MMPs reduced the ability of tumor cell to migrate and invade in vitro. Further, injection of astrocyte media-conditioned breast cancer cells in mice showed increased invasive activity to the brain and other distant sites. More importantly, blocking the preconditioned tumor cells with broad spectrum MMP inhibitor decreased the invasion and metastasis of the tumor cells, in particular to the brain in vivo. Collectively, our data implicate astrocyte-derived MMP-2 and MMP-9 as critical players that facilitate tumor cell migration and invasion leading to brain metastasis. Citation Format: Ling Wang, Stephanie Cossette, Kevin Rarick, Jill Gershan, Michael Michael, David Harder, Ramani Ramchandran. Astrocytes directly influence tumor cell invasion and metastasis in vivo. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-145. doi:10.1158/1538-7445.AM2014-LB-145

Abstract 167: Roles of adipocytes and M2-macrophages in high-fat diet-stimulated lymph node metastasis of B16F10 melanoma

Abstract The tumor microenvironment consists of a number of distinct cell types including tumor cells, fibroblasts, endothelial cells, immune cells, and adipocytes, and produces a wide variety of factors, which contribute to tumor progression. We previously observed that high-fat diet (HFD) feeding stimulates solid tumor growth and lymph node (LN) metastasis in mice subcutaneously injected with B16F10 melanoma cells. We also observed that HFD feeding increases the number of lipid vacuoles and M2-macrophage (M2-Mϕ)s as well as the expression of various cytokines/growth factors in tumor tissues. In the present study, we noted that HFD increased the expression of CCR7 in the tumor. The concentrations of CCL19 and CCL21, the CCR7 ligands, were significantly higher in the LN than those in tumor, and HFD feeding increased the concentrations of these ligands in the LN with negligible changes in the tumor tissue creating higher concentration gradients of these two ligands between the LN and tumor. In order to explore the interactions between tumor cells, adipocytes, lymphatic endothelial cell (LEC)s, and/or M2-Mϕs, we established in vitro co-culture models involving 3 distinct cell types. The mRNA levels of cytokines and growth factors were increased in B16F10 cells and M2-Mϕs when B16F10 cells, M2-Mϕs, and/or mature adipocyte (MA)s were co-cultured in a transwell system. Among these cytokines/growth factors, the mRNA levels of MCP-1 were synergistically increased in B16F10 cells when co-cultured with M2-Mϕs and MAs. The migration of monocytes was tremendously elevated when media conditioned by B16F10 cells/M2-Mϕs/MAs co-cultures was used as a chemoattractant. Furthermore, MAs increased the expression of CCR7 mRNA in B16F10 cells and the expression of CCL19 and CCL21 mRNAs in LECs. These results indicate that in HFD-fed mice, adipocytes induce MCP-1 expression and monocyte infiltration which play important roles in solid tumor growth and LN metastasis. Additionally, adipocyte-stimulated activation of CCL19, CCL21/CCR7 axis in lymphatic endothelial cells and tumor cells helps tumor cells to enter the lymphatic vessels and increased ligand concentration gradients between the LN and tumor facilitate tumor cell migration to the LN. Citation Format: Han Jin Cho, Jae In Jung, Yoo Jin Jung, Ki Won Lee, Mi-Kyung Sung, Jung Han Yoon Park. Roles of adipocytes and M2-macrophages in high-fat diet-stimulated lymph node metastasis of B16F10 melanoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 167. doi:10.1158/1538-7445.AM2014-167

Protocadherin 9 inhibits epithelial–mesenchymal transition and cell migration through activating GSK-3β in hepatocellular carcinoma

Protocadherin 9 (PCDH9) was found frequently lost in hepatocellular carcinoma (HCC). Here we investigated the role of PCDH9 in the development of HCC. We confirmed that PCDH9 was down-regulated in HCC tissues and cell lines compared with the adjacent non-tumor tissues. PCDH9 downregulation was significantly associated with malignant portal vein invasion of HCC patients. Gain- and loss-of-function studies revealed that downregulation of PCDH9 facilitated tumor cell migration and epithelial–mesenchymal transition (EMT). We identified PCDH9 as a novel regulator of EMT by increasing the activity of GSK-3β and inhibiting Snail1, indicating its potential therapeutic value for reducing metastasis of HCC.

The Emerging Role of QSOX1 in Cancer

Quiescin sulfhydryl oxidase 1 (QSOX1) is an enzyme that oxidizes thiols during protein folding, reducing molecular oxygen to hydrogen peroxide. Tumor cells may take advantage of oxidative environments at different stages of tumorigenesis, but QSOX1 may also serve additional functions in tumors. Several groups have reported the over-expression of QSOX1 in breast, pancreas, and prostate cancers. A consensus is building that QSOX1 over-expression is important during tumor cell invasion, facilitating tumor cell migration at the tumor-stroma interface. As such, QSOX1 may be considered a prognostic indicator of metastatic potential or even indicate that cancer is present in a host. However, some controversy exists between QSOX1 as a marker of poor or favorable outcome in breast cancer. More studies are required to reveal what advantage QSOX1 provides to breast and other types of cancer. More specifically, it is critical to learn which tumor types over-express QSOX1 and use its enzymatic activity to their advantage. As interest increases in understanding the mechanisms of tumorigenesis within the extracellular matrix and how tumor cells influence fibroblasts and other stromal cells, QSOX1 may be revealed as an important player in cancer detection and prognosis. Defining the mechanism(s) of QSOX1 activity in tumors and in in vivo models will provide important insights into how to target QSOX1 with anti-neoplastic agents.

Effects of microRNA-30a on migration, invasion and prognosis of hepatocellular carcinoma.

The role of microRNA-30a (miR-30a) deregulation in tumor progression and its downstream signaling pathways remain unknown. Here we confirmed significant downregulation of miR-30a in hepatocellular carcinoma (HCC) tissues and cell lines compared with non-tumor counterparts. MiR-30a downregulation was significantly associated with worse disease-free survival (DFS) of HCC patients. Gain- and loss-of-function studies revealed that downregulation of miR-30a facilitated tumor cell migration, invasion and epithelial-mesenchymal transition (EMT). We identified SNAI1 as a direct target of miR-30a and demonstrated miR-30a as a novel regulator of EMT by targeting SNAI1, indicating its potential therapeutic value for reducing invasion and metastasis of HCC.