Aggressive Local Invasion Research Articles

Mouse model recapitulates the phenotypic heterogeneity of human adult T-cell leukemia/lymphoma in bone

Adult T-cell leukemia/lymphoma has a unique relationship to bone including latency in the marrow, and development of bone invasion, osteolytic tumors and humoral hypercalcemia of malignancy. To study these conditions, we established and characterized a novel mouse model of ATL bone metastasis. Patient-derived ATL cell lines including three that do not express HTLV-1 oncoprotein Tax (ATL-ED, RV-ATL, TL-Om1), an in vitro transformed human T-cell line with high Tax expression (HT-1RV), and an HTLV-1 negative T-cell lymphoma (Jurkat) were injected intratibially into NSG mice, and were capable of proliferating and modifying the bone microenvironment. Radiography, μCT, histopathology, immunohistochemistry, plasma calcium concentrations, and qRT-PCR for several tumor-bone signaling mRNAs were performed. Luciferase-positive ATL-ED bone tumors allowed for in vivo imaging and visualization of bone tumor growth and metastasis over time. ATL-ED and HT-1RV cells caused mixed osteolytic/osteoblastic bone tumors, TL-Om1 cells exhibited minimal bone involvement and aggressive local invasion into the adjacent soft tissues, Jurkat cells proliferated within bone marrow and induced minimal bone cell response, and RV-ATL cells caused marked osteolysis. This mouse model revealed important mechanisms of human ATL bone neoplasms and will be useful to investigate biological interactions, potential therapeutic targets, and new bone-targeted agents for the prevention of ATL metastases to bone.

Oxidative stress and deregulations in base excision repair pathway as contributors to gallbladder anomalies and carcinoma – a study involving North-East Indian population

Gallbladder cancer (GBC) is a fatal condition with dismal prognosis and aggressive local invasiveness; and with uncharacterised molecular pathology relating to non-specific therapeutic modalities. Given the importance of oxidative stress in chronic diseases and carcinogenesis, and the lacunae in literature regarding its role in gallbladder diseases, this study aimed to study the involvement of oxidative stress and deregulation in the base excision repair (BER) pathway in the pathogenesis of gallbladder diseases including GBC. This study involved patients from the North-East Indian population, where the numbers of reported cases are increasing rapidly and alarmingly. Oxidative stress, based on 8-OH-dG levels, was found to be significantly higher in gallbladder anomalies (cholelithiasis [CL] and cholecystitis [CS]) and GBC at the plasma and DNA level, and was associated with GBC severity. The expressions of key BER pathway genes were downregulated in gallbladder anomalies and GBC compared to controls, and in GBC compared to both non-neoplastic controls and gallbladder anomalies. Expression of XRCC1 and hOGG1 was significantly associated with both susceptibility and severity of GBC. The XRCC1 codon280 polymorphism was associated with disease susceptibility; and significantly higher oxidative stress was observed in hOGG1 genotypic variants. The genomes of GBC patients were found to be more hypermethylated compared to controls, with the promoters of XRCC1 and hOGG1 being hypermethylated and, therefore, being silenced. This study underlined the prognostic significance of the oxidative stress marker 8-OH-dG and BER pathway genes, especially hOGG1 and XRCC1, in gallbladder anomalies and GBC, as well as stated their potential for therapeutic targeting.

Abstract 5122: Obesity promotes tumor growth, reduces breast tumor latency and correlates with neovascularization

Abstract Obesity is associated with an increased risk and a poor prognosis for both ER+ and ER- breast cancers (BC). To date, however, few studies have focused on the contribution of obesity to BC. In addition, there is a paucity of in vivo models that reliably recapitulate postmenopausal obesity related to BC development and progression. The goal of this study was to determine whether interactions between adipocytes and breast tumor cells promote BC growth and progression and to identify the underlying mechanism(s) responsible. We found that MDA-MB-436 and MCF-7 BC cells, when treated with the conditioned media of adipocytes from obese individuals (Ad-CM), upregulated a number of angiogenic factors including VEGF-A, Ang-1 and bFGF and suppressed the angiogenic inhibitor Tsp-1. Ad-CM stimulated migration and invasion of MDA-MB-436 and MCF-7 (human) and E-Wnt and M-Wnt (mouse) BC cells. Interestingly, the cellular proliferation rate in response to Ad-CM was stimulated only in the ER+ MCF-7 and E-Wnt cells but not in the ER- BC cells, suggesting that Ad-CM may affect proliferation via an ER-dependent mechanism. After pretreatment with Ad-CM, MDA-MB-436, MCF-7 or M-Wnt BC cells exhibited significantly enhanced EC recruitment as well. Utilizing two different breast tumor models, an orthotopic model (ER-: luciferase-labeled MDA-436 cells injected into the mammary fat pad of SCID mice) and a transgenic model (ER+: doxycycline-driven conditional MMTV/TWNT/luciferase expression), we investigated whether postmenopausal obesity reduces breast tumor latency, promotes angiogenesis and accelerates tumor growth. To model the effect of obesity on postmenopausal BC, mice were ovariectomized (OVX) before inducing obesity via a high-fat diet (HFD) regimen. In the ER- BC model, obese mice had significantly higher tumor frequency, higher tumor volume, and significantly lower median survival. In the ER+ tumor model, obese mice displayed significantly higher tumor frequency, a significantly shorter tumor latency period and a significantly lower median survival time. Tumors in OVX/HFD animals had significantly higher microvessel density (MVD) and an increased number of SMA+ mature vessels. A majority of tumors in OVX/HFD mice displayed aggressive local invasion into the surrounding fat pad and muscle. Proangiogenic factors such as IL-6 (Interleukin-6) and Lcn2 (lipocalin 2) were ~2-fold higher in the sera of obese tumor-bearing mice as compared to controls. Our data suggest that postmenopausal obesity reduces breast tumor latency and promotes aggressive tumor growth via increased angiogenesis. Ongoing studies in our laboratory are investigating the mechanism(s) by which an obesogenic microenvironment mediates these effects. *Authors contributed equally. This work was supported by NIH RO1CA185530. Citation Format: Roopali Roy*, Jiang Yang*, Takaya Shimura, Lauren Merritt, Adelle Dagher, Lewis Chodosh, Marsha A. Moses. Obesity promotes tumor growth, reduces breast tumor latency and correlates with neovascularization [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5122.

Chemokine CCL4 Induces Vascular Endothelial Growth Factor C Expression and Lymphangiogenesis by miR-195-3p in Oral Squamous Cell Carcinoma.

The inflammatory chemokine (C–C motif) ligand 4 (CCL4) plays an important role in the pathogenesis and progression of cancer. In particular, higher serum CCL4 levels in patients with oral squamous cell carcinoma (OSCC) are associated with a more advanced stage of disease. OSCC accounts for approximately 95% of oral cancer in Taiwan and has a poor prognosis, due to aggressive local invasion and metastasis, leading to recurrence. OSCC spreads preferentially through lymphatic vessels and has the propensity to metastasize to the cervical lymph nodes even in the early stage of disease. Vascular endothelial growth factor C (VEGF-C) is an essential regulator of lymphangiogenesis. In particular, VEGF-C is specific to lymphatic vessel development, and VEGF-C expression levels have been found to directly correlate with lymph node metastasis in OSCC. However, it is unclear as to whether CCL4 correlates with VEGF-C expression and lymphangiogenesis in OSCC. We found that CCL4 increased VEGF-C expression and promoted lymphangiogenesis in oral cancer cells in vitro and in vivo. miR-195-3p mimic reversed CCL4-enhanced VEGF-C expression. CCL4 stimulation of oral cancer cells augmented JAK2 and STAT3 phosphorylation. Thus, CCL4 may be a new molecular therapeutic target for inhibition of lymphangiogenesis and metastasis in OSCC.

Ephrin-B2 reverse signaling regulates progression and lymph node metastasis of oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) is a common malignant tumor of the head and neck and frequently metastasizes to cervical lymph nodes. Aggressive local invasion and metastasis of OSCC are significant factors for poor prognosis. In this study, we investigated whether ephrin-B2 expressed in OSCC contributed to tumor progression and lymph node metastasis. Clinical specimens from patients with OSCC had robust ephrin-B2-positive tumor cells and ephrin-B2 protein level was associated with clinical stage, lymph node metastasis, and poor survival outcomes. We also determined that ephrin-B2 protein level was increased in OSCC cell lines compared to normal human oral keratinocytes and that its levels were associated with the migratory and invasive potential of OSCC cell lines. Transfection of an EFNB2–specific small interfering RNA (siRNA) into SAS-L1 cells significantly reduced proliferation, attachment, migration, and invasion through phosphorylation of the epidermal growth factor receptor, FAK, ERK1/2, p38, AKT, and JNK1/2 pathways. Furthermore, knockdown of EFNB2 significantly suppressed adhesion and transmigration of SAS-L1 cells toward human lymphatic endothelial cells. In addition, the growth rate of tumor xenografts and cervical lymph node metastases of OSCC were suppressed by local injection of EFNB2 siRNA. These results suggest that ephrin-B2 overexpression and activation of the ephrin-B2 reverse signaling pathway in tumor microenvironment in OSCC facilitates progression and lymph node metastasis via enhancement of malignant potential and interaction with surrounding cells.

Peripheral lung adenocarcinomas harboring epithelial growth factor receptor mutations with microRNA-135b overexpression are more likely to invade visceral pleura.

Lung adenocarcinoma, characterized by its early and aggressive local invasion and high metastatic potential, is the most frequently observed histological type of non-small-cell lung cancer (NSCLC). Visceral pleural invasion (VPI) caused by peripheral lung adenocarcinomas is closely associated with the poor prognosis of patients with NSCLC. The association between VPI and some clinicopathological characteristics has been observed in the past few decades. However, the molecular mechanism of VPI in lung adenocarcinomas is unknown. In the present, the expression level of microRNA (miR-)135b and epidermal growth factor receptor (EGFR) mutations using the reverse transcription-quantitative polymerase chain reaction and DNA sequencing, respectively. In addition, the present study aimed at exploring the association between the miR-135b level, EGFR mutations and VPI in peripheral lung adenocarcinoma. The results of the present study demonstrated that miR-135b was significantly upregulated in lung adenocarcinoma compared with adjacent normal tissue and positively associated EGFR mutations in peripheral lung adenocarcinoma. Furthermore, it was identified that lung adenocarcinomas with EGFR mutations and miR-135b overexpression were more likely to invade visceral pleura. Taken together, these findings indicate that miR-135b overexpression is positively associated with mutations to EGFR, which may promote the development of peripheral lung adenocarcinomas by the formation of VPI. This indicates that the two factors may serve as prognostic markers and molecular targets for the treatment of peripheral lung adenocarcinomas.

MicroRNA-452 suppresses pancreatic cancer migration and invasion by directly targeting B-cell-specific Moloney murine leukemia virus insertion site 1.

Pancreatic cancer, one of the most common cancers globally, is the fourth most common cause of cancer-associated mortality in the USA. The 5-year relative survival rate for patients with pancreatic cancer is ~5% and the median survival time is only 6 months. The poor prognosis is mainly due to early and aggressive local invasion and metastasis, as well as dissemination of the pancreatic cancer cells. The present study demonstrated that microRNA-452 (miR-452) was markedly downregulated in pancreatic cancer tissues, particularly in metastatic tumors and pancreatic cancer cell lines. Overexpression of miR-452 significantly inhibited migration and invasion in pancreatic cancer cells. In addition, the molecular mechanism underlying the inhibitory functions of miR-452 in pancreatic cancer was also investigated. The results indicated that B-cell-specific Moloney murine leukemia virus insertion site 1 (BMI1) was a direct target gene of miR-452 in pancreatic cancer. Overexpression of miR-452 inhibited the migration and invasion of pancreatic cancer, at least partially by knockdown of BMI1 expression. The results provided novel insight with potential therapeutic applications for the treatment of metastatic pancreatic cancer.

Gemcitabine-induced heparanase promotes aggressiveness of pancreatic cancer cells via activating EGFR signaling.

Pancreatic cancer (PC), characterized by aggressive local invasion and metastasis, is one of the most malignant cancers. Gemcitabine is currently used as the standard drug for the treatment of advanced and metastatic PC, but with limited efficacy. In this study, we demonstrated that gemcitabine increased the expression of heparanase (HPA1), the only known mammalian endoglycosidase capable of cleaving heparan sulfate, both in vitro and in vivo. Furthermore, overexpression of HPA1 in PC cell lines enhanced proliferation and invasion, accompanied with elevated phosphorylation of EGFR. In addition, we showed that the NF-κB pathway mediated the gemcitabine-induced HPA1 expression. Importantly, we found that an HPA1 inhibitor attenuated gemcitabine-induced invasion of PC cells. Finally, we showed that HPA1 was of negative prognostic value for PC patients. Taken together, our results demonstrated that gemcitabine-induced HPA1 promotes proliferation and invasion of PC cells through activating EGFR, implying that HPA1 may serve as promising therapeutic target in the treatment of PC.

Expression and significance of GRHL2 in esophageal cancer.

Esophageal cancer (EC) is one of the most common causes of cancer-related mortality in the world. Although much effort has been made to improve the 5-year survival rate of patients with EC, it still remains low due to diagnosis at an advanced stage, aggressive local invasion, early metastasis, and resistance to chemotherapy. Although grainyhead-like 2 (GRHL2) has attracted interest since it has been recently identified as a novel suppressor of the epithelial–mesenchymal transition, clinical values of GRHL2 and its relationship with the metastasis-related factors, such as hypoxia-inducible factor 1α (HIF-1α) and vascular endothelial growth factor (VEGF), remain unclear. In order to investigate the expression of GRHL2, HIF-1α, and VEGF, and their correlation with angiogenesis in EC, 63 patients with EC were examined. The expression of GRHL2, HIF-1α, and VEGF in tumor tissues was higher than that in adjacent tissues and was associated with tumor differentiation. GRHL2 expression was significantly correlated with lymph node metastasis and invasion depth, whereas VEGF expression was associated with tumor (TNM) stage. A significant correlation was found between the expression of GRHL2 and HIF-1α. The patients expressing low GRHL2 and high HIF-1α showed significant reduction in both overall survival rate and disease-free survival rate. The results demonstrated that abnormal expression of GRHL2 is common in EC, and low expression of GRHL2 accompanied by a high expression of HIF-1α indicates poor prognosis.

Site-specific gene expression profiling as a novel strategy for unravelling keloid disease pathobiology.

Keloid disease (KD) is a fibroproliferative cutaneous tumour characterised by heterogeneity, excess collagen deposition and aggressive local invasion. Lack of a validated animal model and resistance to a multitude of current therapies has resulted in unsatisfactory clinical outcomes of KD management. In order to address KD from a new perspective, we applied for the first time a site-specific in situ microdissection and gene expression profiling approach, through combined laser capture microdissection and transcriptomic array. The aim here was to analyse the utility of this approach compared with established methods of investigation, including whole tissue biopsy and monolayer cell culture techniques. This study was designed to approach KD from a hypothesis-free and compartment-specific angle, using state-of-the-art microdissection and gene expression profiling technology. We sought to characterise expression differences between specific keloid lesional sites and elucidate potential contributions of significantly dysregulated genes to mechanisms underlying keloid pathobiology, thus informing future explorative research into KD. Here, we highlight the advantages of our in situ microdissection strategy in generating expression data with improved sensitivity and accuracy over traditional methods. This methodological approach supports an active role for the epidermis in the pathogenesis of KD through identification of genes and upstream regulators implicated in epithelial-mesenchymal transition, inflammation and immune modulation. We describe dermal expression patterns crucial to collagen deposition that are associated with TGFβ-mediated signalling, which have not previously been examined in KD. Additionally, this study supports the previously proposed presence of a cancer-like stem cell population in KD and explores the possible contribution of gene dysregulation to the resistance of KD to conventional therapy. Through this innovative in situ microdissection gene profiling approach, we provide better-defined gene signatures of distinct KD regions, thereby addressing KD heterogeneity, facilitating differential diagnosis with other cutaneous fibroses via transcriptional fingerprinting, and highlighting key areas for future KD research.

A Role for Neuregulin-1 in Promoting Keloid Fibroblast Migration via ErbB2-mediated Signaling.

Keloid disease is a fibroproliferative tumour characterised by aggressive local invasion, evident from a clinically and histologically active migrating margin. During combined laser capture microdissection and microarray analysis-based in situ gene expression profiling, we identified upregulation of the polypeptide growth factor neuregulin-1 (NRG1) and ErbB2 oncogene in keloid margin dermis, leading to the hypothesis that NRG1 contributed to keloid margin migration through ErbB2-mediated signalling. The aim of this study was to probe this hypothesis through functional in vitro studies. Exogenous NRG1 addition to keloid and normal skin fibroblasts altered cytokine expression profiles, significantly increased in vitro migration and keloid fibroblast Src and protein tyrosine kinase 2 (PTK2/FAK) gene expression. ErbB2 siRNA knockdown attenuated both keloid fibroblast migration and Src/PTK2 expression, which were not recovered following NRG1 administration, suggesting the NRG1/ErbB2/Src/PTK2 signaling pathway may be a novel regulator of keloid fibroblast migration, and representing a potential new therapeutic target.

Abstract 3522: Cyclins and CDKs regulation and caspase cascade activation by cucurbitacin D induced cell cycle arrest and apoptosis in pancreatic tumor

Abstract Pancreatic cancer has a poor prognosis and very low survival rate over the world. Because pancreatic cancer probably is diagnosed at a late stage, aggressive local invasion, and poor response to chemotherapy. Gemcitabine was the standard treatment for advanced and metastatic pancreatic cancer patients, but it is associated with multiple adverse effects-fever, fatigue, nausea, and drug resistance. Whether cucurbitacin D has any efficacy against human pancreatic cancer was examined in cell culture system. In vitro, cell viability was measured by MTT assay to recognize of cell cytotoxicity. Consequently, cytotoxicity was observed at a low concentration of cucurbitacin D. Wound healing assay and clonogenic assay indicated that cucurubitacin D inhibited the growth of cell growth through cyclins and CDKs regulation, and decreased colony-forming ability. Also, this compound down-regulated expression level of anti-apoptotic protein, Bcl-2, up-regulated of pro-apoptotic molecule Bax, and activated caspase-8, caspase-3 cascade extrinsic pathway. Additionally, PARP, caspase-3 substrate, protein was cleaved by cucurbitacin D treatment. Overall, our study suggest that cucurbitacin D could be a clinical medicine for the treatment of pancreatic cancers. Citation Format: Myeong-Sun Kim, Ji Hye Kim, Jin Mo Ku, Se Hyang Hong, Kangwook Lee, Hyeong Sim Choi, Sang Mi Woo, Jee Yun Chang, Tai Young Kim, Seong Gyu Ko Ko. Cyclins and CDKs regulation and caspase cascade activation by cucurbitacin D induced cell cycle arrest and apoptosis in pancreatic tumor. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3522.

Electrochemotherapy in pancreatic adenocarcinoma treatment: pre-clinical and clinical studies.

BackgroundPancreatic adenocarcinoma is currently one of the deadliest cancers with high mortality rate. This disease leads to an aggressive local invasion and early metastases, and is poorly responsive to treatment with chemotherapy or chemo-radiotherapy. Radical resection is still the only curative treatment for pancreatic cancer, but it is generally accepted that a multimodality strategy is necessary for its management. Therefore, new alternative therapies have been considered for local treatment.ConclusionsChemotherapeutic resistance in pancreatic cancer is associated to a low penetration of drugs into tumour cells due to the presence of fibrotic stroma surrounding cells. In order to increase the uptake of chemotherapeutic drugs into tumour cells, electrochemotherapy can be used for treatment of pancreatic adenocarcinoma leading to an increased tumour response rate. This review will summarize the published papers reported in literature on the efficacy and safety of electrochemotherapy in pre-clinical and clinical studies on pancreatic cancer.

The Association Between Inflammation and Angiogenesis in Human Pancreatic Adenocarcinoma

Pancreatic cancer represents one of the deadliest cancers with a high mortality rate, characterized by an aggressive local invasion and early metastases. This malignancy is poorly responsive to chemotherapy or chemo-radiotherapy. Several proangiogenic factors were associated with pancreatic carcinogenesis, highlighting the importance of using antiangiogenic agents as therapeutic strategy. Further studies suggest the involvement of chronic inflammation in angiogenesis processes in pancreatic carcinogenesis and inflammatory cytokines should be considered as potential biomarkers, as well as therapeutic targets in pancreatic cancer patients.

Pilomatrix Carcinoma: Case Report of a Rare Cutaneous Malignancy with Unique Reconstructive Considerations

Pilomatrix carcinoma is a rare malignancy of the hair follicle characterized by aggressive local invasion, high rates of local recurrence, and metastasis in advanced stages. It is the malignant version of a pilomatrixoma. There is no consensus on optimal management, but current approaches typically involve wide local excision, sentinel lymph node biopsy and local reconstruction with skin grafting.

The Role of miRNAs in the Regulation of Pancreatic Cancer Stem Cells.

Pancreatic ductal adenocarcinoma is currently one of the deadliest cancers with low overall survival rate. This disease leads to an aggressive local invasion and early metastases and is poorly responsive to treatment with chemotherapy or chemoradiotherapy. Several studies have shown that pancreatic cancer stem cells (PCSCs) play different roles in the regulation of drug resistance and recurrence in pancreatic cancer. MicroRNA (miRNA), a class of newly emerging small noncoding RNAs, is involved in the modulation of several biological activities ranging from invasion to metastases development, as well as drug resistance of pancreatic cancer. In this review, we synthesize the latest findings on the role of miRNAs in regulating different biological properties of pancreatic cancer stem cells.

Expression Characteristics of miR-10b in Nasopharyngeal Carcinoma

Aim: Nasopharyngeal carcinoma (NPC) is a highly malignant neoplasm characterized with aggressive local invasion and strong tendency of distant metastasis. MicroRNAs (miRNAs) are small noncoding RNAs that play a critical role in the pathogenesis of various malignant tumors. Our previous study aims to explore miRNAs' expression characteristics in NPC tissue, which is barely unknown. Methods: A total of 45 NPC samples (26 metastatic and 19 nonmetastatic) and 16 chronic nasopharyngitis samples were analyzed. miR-10b level was determined by in situ hybridization using digoxigenin-labeled locked nucleic acid-based probe, and latent membrane protein-1 (LMP-1) expression were detected by immunohistochemistry. Results: We show that miR-10b is differentially expressed in NPC tissues. Furthermore, we correlate the expression level of miR-10b with Epstein-Barr virus encoding LMP-1. Overexpression of miR-10b is also found to relate with the clinical phases of NPC. Conclusion: These findings strongly suggest that miR-10b plays an important role in the NPC development.

VEGF regulates region-specific localization of perivascular bone marrow-derived cells in glioblastoma.

Glioblastoma multiforme (GBM) is characterized by a pathogenic vasculature that drives aggressive local invasion. Recent work suggests that GBM cells recruit bone marrow-derived progenitor cells (BMDC) to facilitate recurrence after radiotherapy, but how this may be achieved is unclear. In this study, we established the spatiotemporal and regional contributions of perivascular BMDCs (pBMDC) to GBM development. We found an increased recruitment of BMDCs to GBM in response to tumor growth and following radiotherapy. However, in this study, BMDCs did not differentiate into endothelial cells directly but rather provided a perivascular support role. The pBMDCs were shown to associate with tumor vasculature in a highly region-dependent manner, with central vasculature requiring minimal pBMDC support. Region-dependent association of pBMDC was regulated by VEGF. In the absence of VEGF, following radiotherapy or antiangiogenic therapy, we documented an increase in Ang2 that regulated recruitment of pBMDCs to maintain the vulnerable central vasculature. Together, our results strongly suggested that targeting pBMDC influx along with radiation or antiangiogenic therapy would be critical to prevent vascular recurrence of GBM.

Induction of pancreatic cancer cell migration by an autocrine epidermal growth factor receptor activation

Pancreatic cancer is characterized by aggressive local invasion and early metastasis formation. Active migration of the pancreatic cancer cells is essential for these processes. We have shown previously that the pancreatic cancer cells lines CFPAC1 and IMIM-PC2 show high migratory activity, and we have investigated herein the reason for this observation. Cell migration was assessed using a three-dimensional, collagen-based assay and computer-assisted cell tracking. The expression of receptor tyrosine kinases was determined by flow-cytometry and cytokine release was measured by an enzyme-linked immunoassay. Receptor function was blocked by antibodies or pharmacological enzyme inhibitors. Both cells lines express the epidermal growth factor receptor (EGFR) as well as its family-member ErbB2 and the platelet-derived growth factor receptor (PDGFR)α, whereas only weak expression was detected for ErbB3 and no expression of PDGFRβ. Pharmacological inhibition of the EGFR or ErbB2 significantly reduced the migratory activity in both cell lines, as did an anti-EGFR antibody. Interestingly, combination of the latter with an anti-PDGFR antibody led to an even more pronounced reduction. Both cell lines release detectable amounts of EGF. Thus, the high migratory activity of the investigated pancreatic cancer cell lines is due to autocrine EGFR activation and possibly of other receptor tyrosine kinases.

Contiguous papillary thyroid cancer and mediastinal lymphoma

Patients with differentiated thyroid cancer and extensive local invasion have a generally poor prognosis. We present a patient with a large papillary thyroid cancer and apparent substernal extension with aggressive local invasion. Sternotomy with an intent to debulk the tumor revealed inoperable disease, but open biopsy unexpectedly revealed a large B-cell mediastinal lymphoma completely enveloping the great vessels and bronchial tree and juxtaposed to a large but noninvasive papillary thyroid cancer. This finding allowed proper curative therapy for what otherwise might have been considered inoperable thyroid cancer with anaplastic transformation. Seven years following diagnosis the patient remains disease free from both the thyroid cancer and mediastinal lymphoma.