Cancer Biology, Epidemiology, and Treatment in the 21st Century: Current Status and Future Challenges From a Biomedical Perspective.

Since the second half of the 20th century, our knowledge about the biology of cancer has made extraordinary progress. Today, we understand cancer at the genomic and epigenomic levels, and we have identified the cell that starts neoplastic transformation and characterized the mechanisms for the invasion of other tissues. This knowledge has allowed novel drugs to be designed that act on specific molecular targets, the immune system to be trained and manipulated to increase its efficiency, and ever more effective therapeutic strategies to be developed. Nevertheless, we are still far from winning the war against cancer, and thus biomedical research in oncology must continue to be a global priority. Likewise, there is a need to reduce unequal access to medical services and improve prevention programs, especially in countries with a low human development index.

COPB2: a transport protein with multifaceted roles in cancer development and progression.

The Coatomer protein complex subunit beta 2 (COPB2) is involved in the formation of the COPI coatomer protein complex and is responsible for the transport of vesicles between the Golgi apparatus and the endoplasmic reticulum. It plays an important role in maintaining the integrity of these cellular organelles, as well as in maintaining cell homeostasis. More importantly, COPB2 plays key roles in embryonic development and tumor progression. COPB2 is regarded as a vital oncogene in several cancer types and has been implicated in tumor cell proliferation, survival, invasion, and metastasis. Here, we summarize the current knowledge on the roles of COPB2 in cancer development and progression in the context of the hallmarks of cancer.

ADMA mediates gastric cancer cell migration and invasion via Wnt/ß-catenin signaling pathway.

OBJECTIVE: To explore the role of ADMA in gastric cancer. METHODS: The specimens of 115 gastric cancer patients were analyzed by ELISA and survival analysis. Functional assays were used to assess the effects of ADMA on gastric cancer cells. Experiments were conducted to detect the signaling pathway induced by ADMA in GC. RESULTS: Gastric cancer patients with high ADMA levels had poor prognosis and low survival rate. Furthermore, high level of ADMA did not affect the proliferation while promoted the migration and invasion of gastric cancer cell. Moreover, ADMA enhanced the epithelial-mesenchymal transition (EMT). Importantly, ADMA positively regulated ß-catenin expression in GC and promoted GC migration and invasion via Wnt/ß-catenin pathway. CONCLUSIONS: ADMA regulates gastric cancer cell migration and invasion via Wnt/ß-catenin signaling pathway and which may be applied to clinical practice as a diagnostic and prognostic biomarker.

Clinicopathologic factors associated with recurrence in parotid carcinoma / Clinicopathologic factors associated with recurrence in parotid carcinoma

Abstract Introduction: Parotid carcinomas have varying histological types and diverse biologic behaviors. Establishing an adequate treatment plan and predicting recurrence is important. Objective: To analyze the risk factors associated with recurrence in our 5 year experience with 30 cases of primary parotid carcinoma undergoing surgery at a single institute. Methods: From January 2009 to December 2013, 30 patients with surgical treatment of parotid carcinoma were identified based on their medical records. Results: The 30 patients were comprised of 17 males and 13 females. Among 11 patients with T4 tumors, seven patients had recurrence. Among seven patients with cervical nodal metastasis, all patient except one had recurrence. Clinically late stages (stage III and IV) showed more common recurrence than early stage (stage I and II) lesions. Lymphovascular invasion was seen in 5 patients, and all patients had recurrence. Among 11 patients with extracapsular spread, 7 patients had recurrence. In 17 patients with high grade carcinomas, ten patients had recurrence. In 13 patients with low grade carcinomas, no patients experienced recurrence. Conclusion: T- and N-stage, clinical stage, lymphovascular invasion, extracapsular spread, and histopathologic grade correlate significantly with recurrence in parotid carcinoma.

Resumo: Introdução: Os carcinomas da parótida têm diferentes tipos histológicos e comportamentos biológicos diversos. O estabelecimento de um plano de tratamento adequado e a previsão de recorrência são muito importantes. Objetivo: Analisar os fatores de risco associados à recorrência em nossa experiência de cinco anos com 30 casos de carcinoma parotídeo primário submetidos a cirurgia em uma única instituição. Método: De janeiro de 2009 a dezembro de 2013, 30 pacientes com tratamento cirúrgico de carcinoma parotídeo foram identificados com base nos prontuários. Resultados: Entre os 30 pacientes, 17 eram homens e 13, mulheres. Dos 11 pacientes com tumores T4, sete apresentaram recorrência. Entre sete pacientes com metástase em linfonodo cervical, todos, exceto um, apresentaram recorrência. Lesões em estágios clínicos tardios (III e IV) apresentaram recorrência mais comumente do que as dos estágios iniciais (I e II). A invasão linfovascular foi observada em cinco pacientes e todos os cinco apresentaram recorrência. Entre 11 pacientes com disseminação extracapsular, sete apresentaram recorrência. Dos 17 pacientes com carcinomas de alto grau, dez apresentaram recorrência. Em 13 pacientes com carcinomas de baixo grau, nenhum apresentou recorrência. Conclusão: Estágios T e N, estágio clínico, invasão linfovascular, disseminação extracapsular e grau histopatológico correlacionam-se de maneira significante com recorrência do carcinoma de parótida.

Microenvironmental influence on microtumour infiltration patterns: 3D-mathematical modelling supported by in vitro studies.

Mathematical modelling approaches have become increasingly abundant in cancer research. Tumour infiltration extent and its spatial organization depend both on the tumour type and stage and on the bio-physicochemical characteristics of the microenvironment. This sets a complex scenario that often requires a multidisciplinary and individually adjusted approach. The ultimate goal of this work is to present an experimental/numerical combined method for the development of a three-dimensional mathematical model with the ability to reproduce the growth and infiltration patterns of a given avascular microtumour in response to different microenvironmental conditions. The model is based on a diffusion-convection reaction equation that considers logistic proliferation, volumetric growth, a rim of proliferative cells at the tumour surface, and invasion with diffusive and convective components. The parameter values of the model were fitted to experimental results while radial velocity and diffusion coefficients were made spatially variable in a case-specific way through the introduction of a shape function and a diffusion-limited-aggregation (DLA)-derived fractal matrix, respectively, according to the infiltration pattern observed. The in vitro model consists of multicellular tumour spheroids (MTSs) of an epithelial mammary tumour cell line (LM3) immersed in a collagen I gel matrix with a standard culture medium ("naive" matrix) or a conditioned medium from adipocytes or preadipocytes ("conditioned" matrix). It was experimentally determined that both adipocyte and preadipocyte conditioned media had the ability to change the MTS infiltration pattern from collective and laminar to an individual and atomized one. Numerical simulations were able to adequately reproduce qualitatively and quantitatively both kinds of infiltration patterns, which were determined by area quantification, analysis of fractal dimensions and lacunarity, and Bland-Altman analysis. These results suggest that the combined approach presented here could be established as a new framework with interesting potential applications at both the basic and clinical levels in the oncology area.

Clinicopathologic factors associated with recurrence in parotid carcinoma.

INTRODUCTION: Parotid carcinomas have varying histological types and diverse biologic behaviors. Establishing an adequate treatment plan and predicting recurrence is important. OBJECTIVE: To analyze the risk factors associated with recurrence in our 5 year experience with 30 cases of primary parotid carcinoma undergoing surgery at a single institute. METHODS: From January 2009 to December 2013, 30 patients with surgical treatment of parotid carcinoma were identified based on their medical records. RESULTS: The 30 patients were comprised of 17 males and 13 females. Among 11 patients with T4 tumors, seven patients had recurrence. Among seven patients with cervical nodal metastasis, all patient except one had recurrence. Clinically late stages (stage III and IV) showed more common recurrence than early stage (stage I and II) lesions. Lymphovascular invasion was seen in 5 patients, and all patients had recurrence. Among 11 patients with extracapsular spread, 7 patients had recurrence. In 17 patients with high grade carcinomas, ten patients had recurrence. In 13 patients with low grade carcinomas, no patients experienced recurrence. CONCLUSION: T- and N-stage, clinical stage, lymphovascular invasion, extracapsular spread, and histopathologic grade correlate significantly with recurrence in parotid carcinoma.

E-cadherin: A determinant molecule associated with ovarian cancer progression, dissemination and aggressiveness.

Ovarian cancer (OC) is the fifth cancer death cause in women worldwide. The malignant nature of this disease stems from its unique dissemination pattern. Epithelial-to-mesenchymal transition (EMT) has been reported in OC and downregulation of Epithelial cadherin (E-cadherin) is a hallmark of this process. However, findings on the relationship between E-cadherin levels and OC progression, dissemination and aggressiveness are controversial. In this study, the evaluation of E-cadherin expression in an OC tissue microarray revealed its prognostic value to discriminate between advanced- and early-stage tumors, as well as serous tumors from other histologies. Moreover, E-cadherin, Neural cadherin (N-cadherin), cytokeratins and vimentin expression was assessed in TOV-112, SKOV-3, OAW-42 and OV-90 OC cell lines grown in monolayers and under anchorage-independent conditions to mimic ovarian tumor cell dissemination, and results were associated with cell aggressiveness. According to these EMT-related markers, cell lines were classified as mesenchymal (M; TOV-112), intermediate mesenchymal (IM; SKOV-3), intermediate epithelial (IE; OAW-42) and epithelial (E; OV-90). M- and IM-cells depicted the highest migration capacity when grown in monolayers, and aggregates derived from M- and IM-cell lines showed lower cell death, higher adhesion to extracellular matrices and higher invasion capacity than E- and IE-aggregates. The analysis of E-cadherin, N-cadherin, cytokeratin 19 and vimentin mRNA levels in 20 advanced-stage high-grade serous human OC ascites showed an IM phenotype in all cases, characterized by higher proportions of N- to E-cadherin and vimentin to cytokeratin 19. In particular, higher E-cadherin mRNA levels were associated with cancer antigen 125 levels more than 500 U/mL and platinum-free intervals less than 6 months. Altogether, E-cadherin expression levels were found relevant for the assessment of OC progression and aggressiveness.

Linoleic acid induces migration and invasion through FFAR4- and PI3K-/Akt-dependent pathway in MDA-MB-231 breast cancer cells.

An increased risk of developing breast cancer has been associated with high levels of dietary fat intake. Linoleic acid (LA) is an essential fatty acid and the major ω-6 polyunsaturated fatty acid in occidental diets, which is able to induce inappropriate inflammatory responses that contribute to several chronic diseases including cancer. In breast cancer cells, LA induces migration. However, the signal transduction pathways that mediate migration and whether LA induces invasion in MDA-MB-231 breast cancer cells have not been studied in detail. We demonstrate here that LA induces Akt2 activation, invasion, an increase in NFκB-DNA binding activity, miR34a upregulation and miR9 downregulation in MDA-MB-231 cells. Moreover, Akt2 activation requires EGFR and PI3K activity, whereas migration and invasion are dependent on FFAR4, EGFR and PI3K/Akt activity. Our findings demonstrate, for the first time, that LA induces migration and invasion through an EGFR-/PI3K-/Akt-dependent pathway in MDA-MB-231 breast cancer cells.

Embryonic stem cells markers Oct4 and Nanog correlate with perineural invasion in human salivary gland mucoepidermoid carcinoma.

BACKGROUND: Mucoepidermoid carcinoma (MEC) is the most common salivary gland malignancy and is successfully treated by surgery and radiation. However, some patients have recurrent tumours and in these cases, few treatments options are available. Cancer stem cells (CSC) have been observed and isolated from different solid tumours based on the expression of stem cell markers. These cells are associated with tumour initiation, progression as well as treatment resistance. In this study, the expression of stem cell markers CD44, Bmi1, Oct4 and Nanog was evaluated in non-neoplastic salivary tissue and in MEC. METHODS: Twenty-eight samples of MEC and their corresponding non-neoplastic salivary tissue were examined by immunohistochemistry and the stem cell markers expression was correlated with histological and clinical parameters. RESULTS: CD44 was expressed in the membrane of serous and mucous acini as well as in the ductal cells in normal gland tissue. Bmi1, Oct4 and Nanog were mainly expressed in ductal structures. In MEC, CD44 and Bmi1 showed strong expression in all types of neoplastic cells and both markers revealed intense expression in tumour invasive front. Oct4 and Nanog protein expression was associated with desmoplasia and perineural invasion. Only Oct4 positive tumours were associated with dissociative growth pattern and committed margins. CONCLUSION: The stem cell markers CD44, Bmi1, Oct4 and Nanog are frequently expressed in MEC in relation to normal salivary gland and Oct4 and Nanog expression may contribute to aggressiveness and worst prognosis in MEC patients.

Blood flow velocity in monocular retinoblastoma assessed by color doppler

OBJECTIVE: To analyze the flow of retrobulbar vessels in retinoblastoma by color Doppler imaging. METHODS: A prospective study of monocular retinoblastoma treated by enucleation between 2010 and 2014. The examination comprised fundoscopy, magnetic resonance imaging, ultrasonography and color Doppler imaging. The peak blood velocities in the central retinal artery and central retinal vein of tumor-containing eyes (tuCRAv and tuCRVv, respectively) were assessed. The velocities were compared with those for normal eyes (nlCRAv and nlCRVv) and correlated with clinical and pathological findings. Tumor dimensions in the pathological sections were compared with those in magnetic resonance imaging and ultrasonography and were correlated with tuCRAv and tuCRVv. In tumor-containing eyes, the resistivity index in the central retinal artery and the pulse index in the central retinal vein were studied in relation to all variables. RESULTS: Eighteen patients were included. Comparisons between tuCRAv and nlCRAv and between tuCRVv and nlCRVv revealed higher velocities in tumor-containing eyes (p <0.001 for both), with a greater effect in the central retinal artery than in the central retinal vein (p =0.024). Magnetic resonance imaging and ultrasonography measurements were as reliable as pathology assessments (p =0.675 and p =0.375, respectively). A positive relationship was found between tuCRAv and the tumor volume (p =0.027). The pulse index in the central retinal vein was lower in male patients (p =0.017) and in eyes with optic nerve invasion (p =0.0088). CONCLUSIONS: TuCRAv and tuCRVv are higher in tumor-containing eyes than in normal eyes. Magnetic resonance imaging and ultrasonography measurements are reliable. The tumor volume is correlated with a higher tuCRAv and a reduced pulse in the central retinal vein is correlated with male sex and optic nerve invasion.

Blood flow velocity in monocular retinoblastoma assessed by color Doppler.

OBJECTIVE: To analyze the flow of retrobulbar vessels in retinoblastoma by color Doppler imaging. METHODS: A prospective study of monocular retinoblastoma treated by enucleation between 2010 and 2014. The examination comprised fundoscopy, magnetic resonance imaging, ultrasonography and color Doppler imaging. The peak blood velocities in the central retinal artery and central retinal vein of tumor-containing eyes (tuCRAv and tuCRVv, respectively) were assessed. The velocities were compared with those for normal eyes (nlCRAv and nlCRVv) and correlated with clinical and pathological findings. Tumor dimensions in the pathological sections were compared with those in magnetic resonance imaging and ultrasonography and were correlated with tuCRAv and tuCRVv. In tumor-containing eyes, the resistivity index in the central retinal artery and the pulse index in the central retinal vein were studied in relation to all variables. RESULTS: Eighteen patients were included. Comparisons between tuCRAv and nlCRAv and between tuCRVv and nlCRVv revealed higher velocities in tumor-containing eyes (p < 0.001 for both), with a greater effect in the central retinal artery than in the central retinal vein (p = 0.024). Magnetic resonance imaging and ultrasonography measurements were as reliable as pathology assessments (p = 0.675 and p = 0.375, respectively). A positive relationship was found between tuCRAv and the tumor volume (p = 0.027). The pulse index in the central retinal vein was lower in male patients (p = 0.017) and in eyes with optic nerve invasion (p = 0.0088). CONCLUSIONS: TuCRAv and tuCRVv are higher in tumor-containing eyes than in normal eyes. Magnetic resonance imaging and ultrasonography measurements are reliable. The tumor volume is correlated with a higher tuCRAv and a reduced pulse in the central retinal vein is correlated with male sex and optic nerve invasion.

Label-free proteomic analysis of breast cancer molecular subtypes.

To better characterize the cellular pathways involved in breast cancer molecular subtypes, we performed a proteomic study using a label-free LC-MS strategy for determining the proteomic profile of Luminal A, Luminal-HER2, HER2-positive, and triple-negative (TN) breast tumors compared with healthy mammary tissue. This comparison aimed to identify the aberrant processes specific for each subtype and might help to refine our understanding regarding breast cancer biology. Our results address important molecular features (both specific and commonly shared) that explain the biological behavior of each subtype. Changes in proteins related to cytoskeletal organization were found in all tumor subtypes, indicating that breast tumors are under constant structural modifications to invade and metastasize. We also found changes in cell-adhesion processes in all molecular subtypes, corroborating that invasiveness is a common property of breast cancer cells. Luminal-HER2 and HER2 tumors also presented altered cell cycle regulation, as shown by the several DNA repair-related proteins. An altered immune response was also found as a common process in the Luminal A, Luminal-HER2, and TN subtypes, and complement was the most important pathway. Analysis of the TN subtype revealed blood coagulation as the most relevant biological process.

Adipose tissue-derived stem cells promote pancreatic cancer cell proliferation and invasion.

To explore the effects of adipose tissue-derived stem cells (ADSCs) on the proliferation and invasion of pancreatic cancer cells in vitro and the possible mechanism involved, ADSCs were cocultured with pancreatic cancer cells, and a cell counting kit (CCK-8) was used to detect the proliferation of pancreatic cancer cells. ELISA was used to determine the concentration of stromal cell-derived factor-1 (SDF-1) in the supernatants. RT-PCR was performed to detect the expression of the chemokine receptor CXCR4 in pancreatic cancer cells and ADSCs. An in vitro invasion assay was used to measure invasion of pancreatic cancer cells. SDF-1 was detected in the supernatants of ADSCs, but not in pancreatic cancer cells. Higher CXCR4 mRNA levels were detected in the pancreatic cancer cell lines compared with ADSCs (109.3 ± 10.7 and 97.6 ± 7.6 vs 18.3 ± 1.7, respectively; P<0.01). In addition, conditioned medium from ADSCs promoted the proliferation and invasion of pancreatic cancer cells, and AMD3100, a CXCR4 antagonist, significantly downregulated these growth-promoting effects. We conclude that ADSCs can promote the proliferation and invasion of pancreatic cancer cells, which may involve the SDF-1/CXCR4 axis.

Adipose tissue-derived stem cells promote pancreatic cancer cell proliferation and invasion

To explore the effects of adipose tissue-derived stem cells (ADSCs) on the proliferation and invasion of pancreatic cancer cells in vitro and the possible mechanism involved, ADSCs were cocultured with pancreatic cancer cells, and a cell counting kit (CCK-8) was used to detect the proliferation of pancreatic cancer cells. ELISA was used to determine the concentration of stromal cell-derived factor-1 (SDF-1) in the supernatants. RT-PCR was performed to detect the expression of the chemokine receptor CXCR4 in pancreatic cancer cells and ADSCs. An in vitro invasion assay was used to measure invasion of pancreatic cancer cells. SDF-1 was detected in the supernatants of ADSCs, but not in pancreatic cancer cells. Higher CXCR4 mRNA levels were detected in the pancreatic cancer cell lines compared with ADSCs (109.3±10.7 and 97.6±7.6 vs 18.3±1.7, respectively; P<0.01). In addition, conditioned medium from ADSCs promoted the proliferation and invasion of pancreatic cancer cells, and AMD3100, a CXCR4 antagonist, significantly downregulated these growth-promoting effects. We conclude that ADSCs can promote the proliferation and invasion of pancreatic cancer cells, which may involve the SDF-1/CXCR4 axis.

The invasion mode of GH(3) cells is conditioned by collagen subtype, and its efficiency depends on cell-cell adhesion.

The adaptation of GH(3) cells to different microenvironments is a consequence of a partial compromise with the tumor phenotype. A collagen type IV enriched microenvironment favors an invasive phenotype and increases the substrate adhesion capacity, whereas it decreases the phosphorylation of the regulatory myosin light chain and the aggregation capacity. In contrast, the higher internal tension and increased aggregation capacity induced by collagen type I/III are factors that reduce the invasion rate. Our results show, for the first time, the importance of collagen subtypes in determining the migratory strategy: collagen I/III favors mesenchymal-like motility, whereas collagen type IV induces an ameboid-type displacement. The reciprocal modulation of the myosin light chain kinase and the Rho-kinase determines the invasive capacity through changes in tissue cohesion, extracellular matrix affinity, regulatory myosin light chain phosphorylation and spatial distribution. The collagen subtype determines which of the mechano-transduction signaling pathways will regulate the tensional homeostasis and affect the invasion ability as well as the preferred migration strategy of the cells.

Effect of sulfated glycosaminoglycans on tumor invasion and metastasis.

Metastasis is the most devastating aspect of the tumor, being the main cause of morbidity and mortality in cancer patients. The events that lead to tumor invasion and metastasis depend fundamentally on the initial aquisition of a mesenchymal phenotype by the primary carcinoma, which provides the necessary machinary for invasion, intravasation, vascular transport, extravasation and tumor colonization. These events are orquestrated by different growth factors, proteoglycans and adhesion molecules, acting at the surface of cells. The anticoagulant heparin binds several of these molecules and can regulate the interactions that occur during tumor invasion and metastasis. For example, heparin modulates the binding of FGF-2 to its tyrosine kinase receptor during tumor proliferation, and the binding of growth factors involved in epithelial to mesenchymal transition during tumor invasion. It also binds P-selectin on activated platelets, preventing tumor cell-platelet interaction during hematogeneous metastasis. In this review, we discuss the role of sulfated glycosaminoglycans during tumor invasion and metastasis, and the possible therapeutic use of heparin analogs on cancer treatment.

Rab5 in the regulation of cell motility and invasion.

Cellular invasion requires careful regulation of the cell migration and apoptotic signaling cascades, allowing cell movement and survival of the emigrating populations. Components of the endosomal machinery are involved in these processes, and in particular the role of small GTPases of the Rab family has become appreciated. Rab5 is best known for its role in regulating the trafficking of early endosomes, however, it has recently been appreciated to associate with and regulate the routing of complexes containing integrins, the primary cellular receptors for the extracellular matrix. The association regulates the spatio temporal activation of signals of downstream growth factors and integrins. Rab proteins have also been linked to apoptosis mediated by cell surface death receptors, which elicit the activation of the death cascade via activation of caspase 8. Recently, the link between trafficking, apoptosis and cell migration was strengthened, as Rab5 was determined to work in conjunction with caspase 8 in promoting tumor cell motility and metastasis by regulating ß1 integrin traffic. The capacity to connect and regulate these pathways identifies Rab5 as a key player in future studies of cell migration and tumor dissemination.

Osteoclast-derived matrix metalloproteinase-9 directly affects angiogenesis in the prostate tumor-bone microenvironment.

In human prostate to bone metastases and in a novel rodent model that recapitulates prostate tumor-induced osteolytic and osteogenic responses, we found that osteoclasts are a major source of the proteinase, matrix metalloproteinase (MMP)-9. Because MMPs are important mediators of tumor-host communication, we tested the effect of host-derived MMP-9 on prostate tumor progression in the bone. To this end, immunocompromised mice that were wild-type or null for MMP-9 received transplants of osteolytic/osteogenic-inducing prostate adenocarcinoma tumor tissue to the calvaria. Surprisingly, we found that that host MMP-9 significantly contributed to prostate tumor growth without affecting prostate tumor-induced osteolytic or osteogenic change as determined by microcomputed tomography, microsingle-photon emission computed tomography, and histomorphometry. Subsequent studies aimed at delineating the mechanism of MMP-9 action on tumor growth focused on angiogenesis because MMP-9 and osteoclasts have been implicated in this process. We observed (a) significantly fewer and smaller blood vessels in the MMP-9 null group by CD-31 immunohistochemistry; (b) MMP-9 null osteoclasts had significantly lower levels of bioavailable vascular endothelial growth factor-A(164); and (c) using an aorta sprouting assay, conditioned media derived from wild-type osteoclasts was significantly more angiogenic than conditioned media derived from MMP-9 null osteoclasts. In conclusion, these studies show that osteoclast-derived MMP-9 affects prostate tumor growth in the bone microenvironment by contributing to angiogenesis without altering prostate tumor-induced osteolytic or osteogenic changes.

Undersulfation of glycosaminoglycans induced by sodium chlorate treatment affects the progression of C6 rat glioma, in-vivo.

The stimulatory input of extracellular matrix (ECM) components has been implicated in the invasive properties of glioma cells. It has been demonstrated that undersulfation of glycosaminoglycans (GAGs) promoted by sodium chlorate (SC) treatment reduces C6 glioma cell proliferation and adhesion to ECM molecules, in-vitro. In the present study, the authors investigated the involvement of GAG undersulfation in glioma cell growth in the brain parenchyma. The in-vitro treatment of C6 cells with SC and subsequent intracerebral inoculation in vehicle containing SC resulted in a reduced proportion of animals bearing glioma and a reduced tumor mass diameter. It also promoted longer animal survival. Intracerebral inoculation of SC-treated C6 cells in vehicle without SC or the SC treatment after intracerebral implantation of untreated C6 cells did not result in any reduction of tumor growth. Alterations in clinical, hematological and behavioral parameters in the open field were observed near the point of death when tumors presented a greater size. The results suggest an important role of GAGs in glioma growth which possibly affects cell proliferation and/or interactions with the normal tissue environment.

O papel das proteínas da matriz extracelular e das metaloproteinases em carcinomas de cabeca e pescoco: uma atualizacão bibliográfica / The role of matrix extracellular proteins and metalloproteinases in head and neck carcinomas: an updated review

Interacões entre células neoplásicas e constituintes da matriz extracelular (MEC) interferem fortemente no desenvolvimento tumoral, incluindo os localizados em cabeca e pescoco, pois influenciam a proliferacão e sobrevivência celular, bem como a sua capacidade de migrar do sítio primário para outros tecidos e formar metástases. Essa migracão celular é facilitada pela destruicão parcial da MEC, a qual é realizada pelas metaloproteinases (MMPs), que representam uma família de mais de vinte endopeptidases, com atividade controlada pela expressão de inibidores específicos (TIMPs). Diversos estudos utilizando-se de marcadores para constituintes da MEC bem como pelas MMPs têm fornecido informacões adicionais sobre o diagnóstico e prognóstico em carcinomas de cabeca e pescoco. Nesta revisão consideraremos o papel da MEC e das MMPs na progressão desses tumores, enfatizando que não somente a degradacão proteolítica está envolvida neste processo, como também interacões entre vários constituintes da MEC fornecem substrato para regulacão e crescimento destes tumores.