Non-small cell lung cancer belongs to most frequent malignant tumours at all worldwide. Despite significant progress in knowledge about etiopathogenesis and targeted anticancer therapy, basic scientific research in this particular field and development of more effective treatment remains challenging. In case of its inadequate activation, the Hedgehog signaling pathway is involved in non-small cell cancer development. P53 is well known tumour suppressor gene, that serves as anticancer barrier. Its activity is mostly determined by the transcriptional activation of many pro-apoptotic genes, one of which is SIVA-1. Recently, it has been surprisingly shown, that SIVA-1 has also pro-oncogenic properties in a mouse model of non-small cell lung cancer. The aim of this study was to clarify the importance of Hedgehog signaling pathway and protein SIVA-1 and their potential relationship in development and progression of human non-small cell lung cancer. In selected cell lines of human non-small cell lung cancer, expression of each single component of Hedgehog signalign pathway was detected. In the tissue samples of tumour obtained from 39 patients that underwent surgery for non-small cell lung cancer and selected cell lines of the same tumour, expression of SIVA-1 protein was revealed. These findings indicate...

La prise en charge des cancers bronchiques localisés et localement avancés reste un challenge thérapeutique en cas de traitement par radiothérapie ou radio-chimiothérapie avec des taux d’échec importants. Il a été démontré que la Tomographie par Emission de Positons (TEP) au FDG était indispensable dans la stadification et la planification de la radiothérapie des cancers bronchiques non à petites cellules. De nombreux travaux ont proposé d’adapter le traitement de radiothérapie aux données de la TEP du métabolisme (FDG) mais également à partir de la TEP de l’hypoxie. Nous avons au cours des dernières années essayé de définir les différentes stratégies d’adaptation de la radiothérapie à partie des données de l’imagerie fonctionnelle. Dans le premier travail (travail 1), nous avons analysé les différentes méthodes de segmentation de traceurs à faible contraste pour obtenir des méthodes reproductibles et utilisables au cours d’essais thérapeutiques multicentriques. Ce travail a permis de définir une méthode de segmentation pour le FMISO (traceur de l’hypoxie) mais également pour la FLT qui permet de définir la prolifération. Le second travail (travail 2a et 2b) est le résultat de l’étude multicentrique d’augmentation de dose de radiothérapie à partir des données de la TEP FMISO. Dans ce travail, nous avons proposé de réaliser un boost de radiothérapie chez les patients présentant des tumeurs hypoxiques. Il a été démontré qu’une augmentation modérée de la dose de radiothérapie permettait d’obtenir le même contrôle local à 3 mois pour des tumeurs pourtant plus volumineuses et une tendance à un contrôle supérieur à 3 ans chez les patients ayant pu bénéficié d’un boost par rapport à ceux traités à 66Gy (26.5 mois versus 15.3 mois). Les travaux suivants (travaux 3 et 4) s’intéressent à l’hétérogénéité de fixation de la TEP-FDG et aux méthodes de segmentation de ce traceur en per-radiothérapie. Ces données permettent d’envisager des doses de radiothérapie hétérogènes avec des augmentations ciblées sur les volumes les plus hypermétaboliques en pré-traitement ou sur les volumes pour lesquels il persiste une fixation pathologique en cours de traitement. Les travaux 5 et 6 s’intéressent aux corrélations entre les zones les plus hypermétaboliques (FDG) et les zones hypoxiques (FMISO). Dans un premier temps, nous mettons en évidence le manque de corrélation entre ces 2 traceurs puis dans un second temps l’impact dosimétrique des différentes stratégies de radiothérapie adaptative basée sur la TEP du métabolisme ou de l’hypoxie. Dans le dernier travail (travail 7), nous avons comparé les résultats de deux traceurs de l’hypoxie chez des patients traités par chirurgie pour un cancer bronchique ; ces données ont été comparées aux données d’immunohistochimie pour permettre une meilleure connaissance des traceurs de l’hypoxie. L’ensemble de ces travaux doit permettre une meilleure identification des stratégies de radiothérapie adaptative basée sur l’imagerie fonctionnelle par TEP du métabolisme ou de l’hypoxie. / Résumé en anglais non disponible

<p>A multitude of neurologic diseases are increasing in patients that both diminish quality and quantity of life. My dissertation research focused on unraveling the blood-brain barrier’s alterations (BBB), primarily in lung cancer brain metastases, the most common brain metastasis in patients. We optimized a reliable and reproducible mouse model for creating brain metastases using patient derived brain seeking cells of non-small lung cancer (NSCLC) using ultrasound-guided intracardiac injection. I then evaluated brain tissue with qualitative and quantitative immunofluorescence for individual components of the BBB. Using this experimental method, I was able to identify the specific shift of each BBB component over time in NSCLC brain metastases. I then used human brain metastases specimens to demonstrate the clinical relevance of my findings. These results show distinct alterations in the BBB, which have the potential for targeting therapeutic delivery to extend patient survival. I was also able to characterize a novel epithelial-mesenchymal (EMT) phenotype in vertebral metastases of NSCLC in our model, with features similar to those seen in human patients. Most recently, I analyzed patterns of paracellular permeability associated with each BBB component of NSCLC brain metastases which may provide direct passageways for therapeutic delivery. Altogether, this research offered foundational evidence for the future development of targeted novel therapeutics, including nanoparticles. Outside of the brain metastases field, we used an experimental framework to successfully characterize the BBB alterations in a traumatic brain injury model (bTBI). These findings provided the first description of this unique pathology and the framework for developing therapeutics in other neurologic diseases. Although my research work has focused on animal models of disease, future directions based on my research work include the developing a novel 3D BBB-on-chip device to enable high throughput novel therapeutic delivery through the BBB. Long-term, identifying targetable alterations in the restrictive BBB using <i>in vitro</i> and <i>in vivo</i> models provides a potential conduit for effective prevention and treatment of a myriad of neurologic diseases to prolong patient survival and quality of life.</p>

<p>Karcinom bronha je danas u svetu najče&scaron;ći uzrok smrti povezanih sa malignim bolestima. U XX veku je registrovan značajan porast kako incidence, tako i mortaliteta karcinoma bronha u većini zemalja. Medijana&nbsp; preživljavanja u svim stadijumima bolesti se značajno pobolj&scaron;ala poslednjih godina XX veka, ali nedovoljno u odnosu na očekivano. U najvećem broju slučajeva, bolest se otkriva u uznapredovalom stadijumu, kada je radikalno hirur&scaron;ko lečenje kao optimalan vid lečenja nemoguće. Određivanje stadijuma bolesti (stejdžing) je najbitniji segment u evaluaciji svakog bolesnika s karcinomom bronha. Utvrđivanje zahvaćenosti medijastinalnih&nbsp; limfnih čvorova karcinomom je od posebne važnosti, jer je u velikom broju slučajeva upravo nodalni status faktor koji određuje svsishodnost primene hirur&scaron;kog lečenja, radioterapije i hemioterapije, a samim tim i jedan od bitnih faktora prognoze bolesnika sa nemikrocelularnim karcinomom bronha NSCLC. Bolesnici sa dokazanom zahvaćeno&scaron;ću N2 medijastinalnih limfnih čvorova se svrstavaju u IIIA stadijum NSCLC koji je potencijalno resektabilan, dok se bolesnici sa dokazanom zahvaćeno&scaron;ću N3 medijastinalnih limfnih čvorova svrstavaju u IIIB stadijum NSCLC, koji se smatra neresektabilnim. Cilj ove doktorske disertacije je bio da se utvrdi da li postoje prognostički značajni faktori za rezultat lečenja medijastinoskopski dokazanog N2 i N3 stadijuma NSCLC. Studija je bila nerandomizovana, delom retrospektivnog, a delom prospektivnog karaktera. U ispitivanje je uključeno 60 bolesnika lečenih u Institutu za plućne bolesti Vojvodine tokom&nbsp; 2006., 2007. i 2008. godine. Kod svih uključenih bolesnika medijastinoskopijom je dokazana propagacija NSCLC u medijastinalne limfne čvorove. U radu su analizirani sledeći faktori: pol, starost, ECOG performans status, pridružena hronična opstruktivna bolest pluća (HOBP), pridruženo kardiovaskularno oboljenje sa simtomatologijom klasifikovanom prema NYHA, T faktor, lokalizacija i broj medijastinoskopski dokazanih metastatski zahvaćenih limfnih čvorova, vrsta primenjenog&nbsp; lečenja (hemioradioterapija, hemioterapija, operacija), rezultat lečenja (odgovor na terapiju i preživljavanje). Univarijantnom analizom je utvrđeno da su kod bolesnika sa medijastinoskopski dokazanim N2 i N3 stadijumom NSCLC prognostički faktori koji su imali uticaj na lo&scaron;ije preživljavanje bili: ECOG PS 2 (p=0,00000), pridruženo kardivaskularno oboljenja sa simptomatologijom klase NYHA II (p=0,00113), zahvaćenost kontralateralnih medijastinalnih medijastinalnih limfnih čvorova (N3 stadijum) (p=0,000003), dok je uticaj zahvaćenosti vi&scaron;e pozicija ipsilateralnih medijastinalnih limfnih čvorova (multi station N2) bio na granici statističke značajnosti (p=0,05385). Utvrđeno je da bolesnici sa N2 i N3 stadijumom NSCLC lečeni hemioradioterapijom imaju bolju stopu odgovora na primenjenu terapiju u odnosu na bolesnike lečene samo hemioterapijom (p=0,03118), kao i da operativno lečenje primenjeno kod bolesnika koji su imali dobar odgovor na sprovedenu terapiju ima statistički značajan uticaj u vidu boljeg preživljavanja (p=0,00121). Univarijantnom analizom nije utvrđen značajan uticaj sledećih faktora na preživljavanje bolesnika sa N2 i N3 stadijomom NSCLC: pol, starost, pridružena HOBP, skvamozni tip NSCLC i T faktor. Multivarijantnom analizom su kao nezavisni prognostički faktori na preživljavanje bolesnika sa N2 i N3 stadijumom NSCLC utvrđeni klinički N status (bolje preživljavanje ima N2 u odnosu na N3 stadijum) i sprovedena terapija (bolje preživljavanje ima hemioradioterapija u odnosu na hemioterapiju). Dobijeni rezultati navode nas na zaključak da su pozicija i broj zahvaćenih pozicija medijastinalnih limfnih čvorova, koji su utvrđeni medijastinoskopski, kao i sprovođenje multimodalnog lečenja ključni prognostički faktori za preživljavanje bolesnika sa N2 i N3 stadijumom NSCLC.</p> / <p>Lung&nbsp; cancer&nbsp; is&nbsp; the&nbsp; most&nbsp; common cause of cancer&nbsp; related mortality&nbsp; worldwide.&nbsp; Increase&nbsp; in&nbsp; both&nbsp; incidence&nbsp; and mortality&nbsp; of&nbsp; lung&nbsp; cancer&nbsp; was&nbsp; registered&nbsp; throughout&nbsp; 20th century. The median survival in every stage of lung cancer has been improved in last years of 20th century but it is still not satisfactory. In most cases, lung cancer is diagnosed in advanced&nbsp; stage&nbsp; when&nbsp; surgical&nbsp; treatment&nbsp; as&nbsp; the&nbsp; optimal approach&nbsp; is&nbsp; not&nbsp; possible. Staging&nbsp; is&nbsp; the&nbsp; most&nbsp; important element&nbsp; in&nbsp; the&nbsp; evaluation&nbsp; of&nbsp; every&nbsp; lung&nbsp; cancer&nbsp; patient. Mediastinal lymph node involvement is crucial, because in most of the cases nodal staging is factor which determines appropriate use of surgery, radiotherapy and chemotherapy and it is one of the important factors influencing prognosis of lung cancer patients. Patients with proven involvement of ipsilateral&nbsp; mediastinal&nbsp; lymph&nbsp; nodes&nbsp; (N2&nbsp; stage)&nbsp; are categorized&nbsp; in&nbsp; IIIA&nbsp; stage&nbsp; which&nbsp; is&nbsp; considered&nbsp; to&nbsp; be potentially resectable, and patients with proven involvement of&nbsp; contralateral&nbsp; mediastinal&nbsp; lymph&nbsp; nodes&nbsp; (N3&nbsp; stage)&nbsp; are categorized&nbsp; in&nbsp; IIIB&nbsp; stage,&nbsp; which&nbsp; is&nbsp; considered&nbsp; to&nbsp; be nonresectable. The aim of this study was the determination of&nbsp; significant&nbsp; prognostic&nbsp; factors&nbsp; that&nbsp; have&nbsp; influence&nbsp; on treatment&nbsp; and&nbsp; survival&nbsp; of&nbsp; non-small&nbsp; cell&nbsp; lung&nbsp; cancer (NSCLC)&nbsp; patients&nbsp; in&nbsp; stage&nbsp; N2&nbsp; and&nbsp; N3.&nbsp; Study&nbsp; was nonrandomized,&nbsp;&nbsp; partially&nbsp;&nbsp; retrospective&nbsp;&nbsp; and&nbsp;&nbsp; partially prospective. It included 60 patients treated at the Institute for Pulmonary&nbsp; Diseases&nbsp; of&nbsp; Vojvodina&nbsp; during&nbsp; 2006,&nbsp; 2007&nbsp; and 2008. Cancer involvement of mediastinal lymph nodes was determined by mediastinoscopy in every patient. In study we analyzed following factors: gender, age, ECOG performance&nbsp;&nbsp; status,&nbsp;&nbsp; associated&nbsp;&nbsp; chronic&nbsp;&nbsp; obstructive pulmonary&nbsp; disease&nbsp; (COPD),&nbsp; associated&nbsp; cardiovascular disease with symptoms graded by NYHA classification, T status, position and number of involved mediastinal lymph nodes,&nbsp; applied&nbsp; treatment&nbsp; (surgery,&nbsp; chemoradiotherapy, chemotherapy alone), treatment result (response to treatment and&nbsp; survival).&nbsp; Prognostic&nbsp; factors&nbsp; for&nbsp; poorer&nbsp; survival&nbsp; on univariant analysis were ECOG PS 2 (p=0,0000), associated cardiovascular&nbsp;&nbsp; disease&nbsp;&nbsp; with&nbsp;&nbsp; symptoms&nbsp;&nbsp; NYHA&nbsp;&nbsp; II (p=0,00113)&nbsp; and&nbsp; involvement of&nbsp; contralateral&nbsp; mediastinal lymph nodes (N3 stage) (p=0,00003) while multi station N2 disease was borderline significant at level of p=0,05385. It was determined that patients treated with chemoradiotherapy achieved better response to treatment compared to patients treated&nbsp; with&nbsp; chemotherapy&nbsp; alone&nbsp; (p=0,03118).&nbsp; Univariant analyses&nbsp; did&nbsp; not&nbsp; confirm&nbsp; significance&nbsp; of&nbsp; gender,&nbsp; age, associate COPD, squamous cell lung cancer and T factor on survival. Multivariante&nbsp; analyses&nbsp; identified&nbsp; N&nbsp; status&nbsp; (better survival has N2 stage compared to N3 stage of NSCLC) and conducted treatment (better survival has&nbsp; chemoradiotherapy compared to chemotherapy alone) as independent prognostic factors.&nbsp; Our&nbsp; results&nbsp; suggest&nbsp; that&nbsp; position&nbsp; and&nbsp; number&nbsp; of cancer involved&nbsp; mediastinal lymph nodes position,&nbsp; proven by mediastinoscopy, as well as the conducted multimodality treatment are key prognostic factors which might influence the survival of patients with N2 and N3 stage of NSCLC.</p>

Lung cancer is a disease with a high mortality rate for the U.S. Black population. There had been considerable research done on different population demographics, necessary to achieve the Healthy People 2020 overarching goals to eliminate health disparities, gain health equity and maintain quality health. Yet, the African-born Black (AFBB) population has been understudied for nonsmall cell lung cancer (NSCLC). This study sought to determine whether within race differences in stage at diagnosis and treatment of NSCLC exists between AFBB and American-born Blacks (AMBB) populations in the United States. The study data is secondary data collected as part of the National Cancer Institute's Surveillance Epidemiologic and End Result (SEER) Program from 2004-2011. Athough no significant difference was found between AFBB (n = 119) and AMBB (n = 238) relative to NSCLC stage at diagnosis, differences in treatments were found. The proportion of AFBB patients with early stage (I and II) NSCLC who underwent surgery differed significantly from that of AMBB (p < 0.05); AFBB patients were more likely to receive surgical therapy. The proportion of AFBB patients with stages I-IV of the disease who received radiation treatment also differed significantly from that of AMBB patients (p < 0.05); the latter were more likely to receive radiation therapy. Results from logistic regression analysis indicate that AFBB patients were more likely to receive surgical treatment while AMBB patients were more likely to receive radiation treatment. This study outcome can inform other NSCLC research to provide better insights to the cause of the treatment differences within the race from differing birth places, and efficient planning, evaluation of control programs and management of the disease.

Cette thèse porte sur plusieurs technologies de déchargement cellulaire pour les futurs réseaux sans fil avec l’amélioration envisagée sur la efficacité spatiale du spectre et l’efficacité énergétique. Notre recherche concerne deux directions principales, y compris la communication D2D underlaid dans les réseaux cellulaires et le caching proactif au bord de réseau.La première partie de cette thèse contient deux chapitres qui présentent nos résultats de recherche sur les réseaux cellulaire avec D2D underlaid. Notre recherche se focalise sur l’accès opportuniste distribué, dont la performance en termes du débit D2D est optimisé dans deux scénarios: 1) en supposant que l’utilisateur cellulaire avec un trafic saturé peut avoir une probabilité de couverture minimale; 2) en supposant que le trafic discontinu à l’utilisateur cellulaire, dont le délai moyen doit être maintenue au-dessous d’un certain seuil. La deuxième partie de cette thèse se focalise sur les méthodes de caching proactif au bord de réseau, y compris le caching aux petites cellules et aux appareils des utilisateurs. Tout d’abord, nous étudions le placement de contenu probabiliste dans différents types de réseaux et avec différents objectifs d’optimisation. Deuxièmement, pour le caching aux petites cellules, nous proposons un schéma coopérative parmi les petites stations de base, qui exploite le gain combiné du caching coopérative et les techniques de multipoint coordonnée. Les modèles de processus ponctuel nous permet de créer la connexion entre la diversité de transmission en couche PHY et la diversité de contenus stockés. / This thesis focuses on several emerging technologies towards future wireless networks with envisaged improvement on the area spectral efficiency and energy efficiency. The related research involves two major directions, including deviceto- device (D2D) communication underlaid cellular networks and proactive caching at network edge. The first part of this thesis starts with introducing D2D underlaid cellular network model and distributed access control methods for D2D users that reuse licensed cellular uplink spectrum. We aim at optimize the throughput of D2D network in the following two scenarios: 1) assuming always backlogged cellular users with coverage probability constraint, 2) assuming bursty packet arrivals at the cellular user, whose average delay must be kept below a certain threshold. The second part of this thesis focuses on proactive caching methods at network edge, including at small base stations (SBSs) and user devices. First, we study and compare the performance of probabilistic content placement in different types of wireless caching networks and with different optimization objectives. Second, we propose a cooperative caching and transmission strategy in a cluster-centric small cell networks (SCNs), which exploits the combined gain of cache-level cooperation and CoMP technique. Using spatial models from stochastic geometry, we build the connection between PHY transmission diversity and the content diversity in local caches.

Les stations de base à petite échelle (picocellules et femtocellules) seront un des leviers principaux qui permettront d'atteindre l'objectif 1000X, objectif fixé par les grands acteurs du domaine des télécommunications visant à augmenter la capacité des réseaux mobiles sans fil 5G d'un facteur 1000 par rapport aux réseaux 4G. Dans ce type de réseau, l'amplificateur de puissance (PA) est responsable de la majorité de la consommation de puissance de la station de base. Pour minimiser sa consommation de puissance, le PA est polarisé proche de sont point de compression mais avec l'augmentation des largeurs de bande, ce dernier subit des effets de mémoire accrus qui viennent s'ajouter aux problèmes classiques de non-linéarités. Les systèmes de prédistorsion numérique (DPD), et analogique/RF(ARFPD) peuvent être utilisés pour améliorer le compromis linéarité / efficacité des PAs. Cependant pour les pico-cellules et femto-cellules utilisées dans le standard 5G, les prédistorseurs conventionnels ne sont adaptés pour des raisons de complexité et de consommation de puissance.Le modèle "Memory Polynomilal" (MP) est l'un des modèles de prédistorsion les plus attractifs pour modéliser les PAs, fournissant des performances intéressantes avec peu de coefficients. Cependant, la précision de ce modèle se dégrade pour les signaux large bance. Pour palier ce problème, nous proposons un nouveau modèle, le FIR-MP qui combine un filtre FIR au modèle MP classique. Pour valider et quantifier la précision du modèle proposé, nous avons effectué des simulations avec un modèle extrait par mesure de l'amplificateur sur étagère ADL5606 (GaAs 1W HBT PA). Les résultats de ces simulations présentent des améliorations du taux de fuite des canaux adjacents (ACLR) de 7,2 dB et 15,6 dB, respectivement, pour des signaux à 20 MHz et 80 MHz par rapport au modèle MP classique. Le FIR-MP a été également synthétisé en technologie CMOS FDSOI 28 nm. Les résultats de la synthèse ont donné une puissance globale de 9,18 mW and 116,2 mW, respectivement, pour les signaux de 20 MHz and 80 MHz.Basé sur le modèle proposé de FIR-MP, une nouvelle approche à signaux mixtes pour linéariser les PAs a été aussi étudiée. En fait, le filtre numérique FIR améliore la performance de correction de la mémoire sans aucune expansion de la bande passante et la linéarisation en bande de base permet d'éviter l'utilisation de composants RF dans la linéariseur. Ainsi, les contraintes en bande passante requises pour le DAC, les filtres de reconstruction et les blocs RF de l'émetteur sont relâchées comparés aux techniques conventionnelles de linéarisation numériques et RF. Nous avons ainsi étudié l'impact des diverses non-idéalités en utilisant un signal modulé à 80 MHz afin de dériver les exigences pour la mise en œuvre du circuit. Les simulations ont montré qu'une résolution de 8 bits pour les coefficients et un SNR de 60 dB sont nécessaires pour atteindre un ACLR1 supérieur à 45 dBc. Ces résultats constituent un premier signe favorable dans l'optique d'une implémentation matérielle de la solution proposée, étape indispensable pour évaluer précisément sa consommation de puissance et sa complexité pour pouvoir la comparer à l'état de l'art des linéariseurs. / Small-cell base stations (picocells and femtocells) handling high bandwidths (> 100 MHz) will play a vital role in realizing the 1000X network capacity objective of the future 5G wireless networks. Power Amplifier (PA) consumes the majority of the base station power, whose linearity comes at the cost of efficiency. With the increase in bandwidths, PA also suffers from increased memory effects. Digital predistortion (DPD) and analog RF predistortion (ARFPD) tries to solve the linearity/efficiency trade-off. In the context of 5G small-cell base stations, the use of conventional predistorters becomes prohibitively power-hungry.Memory polynomial (MP) model is one of the most attractive predistortion models, providing significant performance with very few coefficients. We propose a novel FIR memory polynomial (FIR-MP) model which significantly augments the performance of the conventional memory polynomial predistorter. Simulations with models extracted on ADL5606 which is a 1 W GaAs HBT PA show improvements in adjacent channel leakage ratio (ACLR) of 7.2 dB and 15.6 dB, respectively, for 20 MHz and 80 MHz signals, in comparison with MP predistorter. Digital implementation of the proposed FIR-MP model has been carried out in 28 nm FDSOI CMOS technology. With a fraction of the power and die area of that of the MP a huge improvement in ACLR is attained.An overall estimated power consumption of 9.18 mW and 116.2 mW, respectively, for 20 MHz and 80 MHz signals is obtained.Based on the proposed FIR-MP model a novel low-power mixed-signal approach to linearize RF power amplifiers (PAs) is presented. The digital FIR filter improves the memory correction performance without any bandwidth expansion and the MP predistorter in analog baseband provides superior linearization. MSPD avoids 5X bandwidth requirement for the DAC and reconstruction filters of the transmitter and the power-hungry RF components when compared to DPD and ARFPD, respectively.The impact of various non-idealities is simulated with ADL5606 (1 W GaAs HBT PA) MP PA model using 80 MHz modulated signal to derive the requirements for the integrated circuit implementation. A resolution of 8 bits for the coefficients and a signal path SNR of 60 dB is required to achieve ACLR1 above 45 dBc, with as little as 9 coefficients in the analog domain. Discussion on the potential circuit architectures of subsystems is provided. It results that an analog implementation is feasible. It will be worth in the future to continue the design of this architecture up to a silicon prototype to evaluate its performance and power consumption.

Lung cancer leads in mortality among all types of cancer in the US and Non-small cell lung cancer (NSCLC) is the major type of lung cancer. Immuno-compromised mice bearing xenografts of human lung cancer cells represent the most common animal models for studying lung cancer biology and for evaluating potential anticancer agents. However, orthotopic lung cancer models based on intrapulmonary injection of suspended cancer cells feature premature leakage of the cancer cells to both sides of the lung within five days, which generates a quick artifact of metastasis and thus belies the development and progression of lung cancer as seen in the clinic. Based on intrapulmonary inoculation of multicellular spheroids (MCS), we have developed the first orthotopic xenograft model of lung cancer that simulates all four clinical stages of NSCLC progression in mice over one month: Stage 1 localized tumor at the inoculation site; Stage 2 multiple tumor nodules or larger tumor nodule on the same side of the lung; Stage 3 cancer growth on heart surface; and Stage 4 metastatic cancer on both sides of the lung. The cancer development was monitored conveniently by in vivo fluorescent imaging and validated by open-chest anatomy, ex vivo fluorescent imaging, and histological studies. The model enjoys high rates of postoperative survival (100%) and parenchymal tumor establishment (88.9%). The roughness of the inoculated MCS is associated negatively with the time needed to develop metastatic cancer (p=0.0299). In addition, we have constructed a co-culture MCS that consisted of A549-iRFP lung cancer cells and WI38 normal human fibroblast cells. The pro-proliferation effect and the high expression of α-smooth muscle actin (α-SMA) by the co-cultured WI38 cells indicated their transformation from normal fibroblasts to cancer-associated fibroblasts (CAFs). The morphology of the co-culture MCS features a round shape, a tight internal structure, and quicker development of roughness. The large roughness value of co-culture MCS suggests that small co-culture MCS could be inoculated into mice lung with a small needle to reduce the surgical trauma. Taken together, a new orthotopic model of NSCLC has been developed, which would facilitate future development of medications against lung cancer.

No description available.

No description available.