Epigenetic mechanisms in gastric cancer: potential new therapeutic opportunities

Gastric cancer (GC) is one of the deadliest malignancies worldwide. Complex disease heterogeneity, late diagnosis, and suboptimal therapies result in the poor prognosis of patients. Besides genetic alterations and environmental factors, it has been demonstrated that alterations of the epigenetic machinery guide cancer onset and progression, representing a hallmark of gastric malignancies. Moreover, epigenetic mechanisms undergo an intricate crosstalk, and distinct epigenomic profiles can be shaped under different microenvironmental contexts. In this scenario, targeting epigenetic mechanisms could be an interesting therapeutic strategy to overcome gastric cancer heterogeneity, and the efforts conducted to date are delivering promising results. In this review, we summarize the key epigenetic events involved in gastric cancer development. We conclude with a discussion of new promising epigenetic strategies for gastric cancer treatment

Immune response to tumor

The immune system of the host responds to tumor growth as it does to infectious agents, with specific (e.g. T cells and antibodies) and non-specific (e.g. natural killer cells and cytokines) effector and regulatory mechanisms. The immune response reduces the number of tumors arising in the host, but is no longer effective against established tumors. Tumor immunotherapy is the attempt to elicit a therapeutic immune response in cancer patients

Terapia molecolare dei sarcomi

Il progetto intende individuare e valutare nuove strategie terapeutiche per i sarcomi muscolo-scheletrici utilizzando approcci multipli. Innanzitutto inibitori specifici verranno utilizzati per bloccare prodotti genici rilevanti per la biologia di questi sarcomi. Gli studi utilizzeranno un ampio pannello di linee cellulari di rabdomiosarcoma, sarcoma di Ewing e osteosarcoma rappresentative dei principali istotipi e varianti geniche, ed anche cellule farmaco-resistenti. Modelli preclinici di crescita e metastatizzazione di cellule di sarcoma in topi immunodepressi saranno utilizzati per la terapia in vivo. Circuiti autocrini mediati dal recettore di tipo 1 dei fattori di crescita insulino-simili (IGF1R) verranno bloccati con l\u2019inibitore di tirosina chinasi NVP-AEW541 o con small interfering RNA (siRNA) e verranno studiati lo stato di fosforilazione di IGF1R e la segnalazione via ERK e AKT. Gli studi cellulari esamineranno proliferazione, apoptosi, crescita in agar e migrazione cellulare dopo trattamento con inibitori di IGF1R da soli o in combinazione con i farmaci citotossici utilizzati per la terapia di questi sarcomi. Verr\ue0 studiato il ruolo della tirosina chinasi SRC nella crescita e nella malignit\ue0 dei sarcomi e ne verr\ue0 inibita l\u2019attivit\ue0 con dasatinib/BMS354825, SU6656 e AP23451. L\u2019attivit\ue0 terapeutica di questi inbitori di SRC verr\ue0 valutata anche in combinazione con inibitori di IGF1R e con farmaci citotossici. CD99 \ue8 una molecola di membrana che scatena l\u2019apoptosi nelle cellule di sarcoma di Ewing quando viene legata da anticorpi agonisti. La funzione di CD99 verr\ue0 indagata mediante specifici siRNA in vitro ed in vivo. Per determinare se CD99 sia un bersaglio terapeutico anche in altri tipi tumorali che lo esprimono si studier\ue0 la risposta ad anticorpi anti-CD99 di sarcomi sinoviali, carcinomi prostatici e leucemie linfoblastiche acute. La miogenina, fattore trascrizionale che controlla il differenziamento muscolare, \ue8 poco espressa dai rabdomiosarcomi scarsamente differenziati. Si valuter\ue0 se l\u2019espressione forzata di miogenina possa indurre differenziamento del rabdomiosarcoma ed inibire crescita tumorale e disseminazione metastatica. Un secondo approccio consister\ue0 nello studio di nuovi farmaci diretti contro bersagli molecolari individuati in altri tumori e non ancora caratterizzati nei sarcomi muscolo-scheletrici. Verr\ue0 valutata in vitro ed in vivo l\u2019efficacia terapeutica di bortezomib (inibitore del proteasoma) e di 17-allilamino geldanamicina (inibitore di heat shock protein 90). Verranno individuati nuovi geni bersaglio e nuovi inibitori farmacologici di tirosina chinasi. Una meta-analisi di tutti i profili di espressione genica disponibili per il rabdomiosarcoma, inclusi quelli di tumori murini generati da questo progetto, permetter\ue0 di delineare vie di segnalazione e geni all\u2019origine di questo tumore e di individuare nuovi bersagli terapeutici. Nuovi inibitori di tirosina chinasi saranno individuati mediante modellazione tridimensionale, identificazione "in silico" di candidati nei database di piccole molecole, sintesi e valutazione biologica delle molecole pi\uf9 promettenti. Infine nuovi modelli di topi geneticamente modificati ed immunodepressi permetteranno di indagare elementi chiave della progressione dei sarcomi quali alterazioni geniche precoci, invasivit\ue0 e metastasi, e di saggiare nuove terapie in condizioni realistiche di crescita tumorale e disseminazione. L'insorgenza e la storia naturale del rabdomiosarcoma verranno studiate nei topi BALBp53Neu (transgenici HER-2 e knockout p53), un modello originale in cui si sviluppano rabdomiosarcomi embrionali pelvici. L'impianto di sarcomi in topi knockout di Rag2 e gamma common, che mancano di risposte T, B ed NK, permetter\ue0 di studiare lo sviluppo della malignit\ue0 in assenza di risposte immuni murine che impediscono crescita e metastatizzazione delle cellule tumorali umane

Commentary on "High throughput views of cancer immune responsiveness" by Wang et al.

The molecular mechanisms underlying responsiveness or unresponsiveness to cancer immunotherapy are mostly unknown at the clinical level. We certainly know many reasons why tumors become immunoresistant, but this is far from being able to demonstrate why (or even better, predict if) a given patient is responsive or unresponsive to a precise inmmunotherapeutic protocol. It is one area in which immunotherapy lags behind pharmacological therapy, as far as molecular determinants of resistance (e.g. MDR1) and pharmacogenomics are concerned. One of the main causes of this state of affairs is the complexity of the immune response and of the relationships among immune system, tumor, and host. As pointed out by Wang et al., it is quite clear that spontaneous inflammatory and immune responses can favor tumor progression and growth. Hence the task of cancer immunotherapy is to turn a detrimental response into a useful one, rather than simply to elicit an immune response where there is none. A further problem is related to sampling. Relevant immune responses take place inside tumors and metastases, or in the lymph node, but we sample peripheral blood to understand what is happening. This is similar to the man who lost his keys in a dark alley but went looking under a lamppost because \u201cat least here is some light\u201d. Now we have high throughput tools to address system complexity. Microarrays simultaneously evaluate the entire transcriptome, or tens of thousands of genetic polymorphisms. Current microarrays are far from perfect, nonetheless they are already yielding a steady flow of important translational and clinical results. The challenge for microarrays, and for other technologies such as proteomics, will be to demonstrate their potency in extracting meaningful results where conventional immunological techniques fail because of unsurmountable sampling difficulties

Is mts1(S100A4) gene involved in the metastatic process modulated by gamma-interferon?

This study investigates the involvement of mts1 (S100A4) in the metastatic process. We have evaluated the levels of mts1 gene in murine cancer cells following modulation of the metastatic ability. We report here that modulation of the expression of mts1 gene in cells derived from a breast murine adenocarcinoma (TS/A) did not correlate with metastatic ability either when pretreated in vitro with gamma-interferon (gamma-IFN) or following transfection with gamma-IFN gene. In another series of experiments we treated the cell lines B16-A and B78H1, both derived from B16 melanoma, with gamma-IFN. An increased expression of mts1 was found only in B16-A, but not B78H 1, correlated with a strong increase in metastatic activity of B16-A clone upon gamma-IFN treatment

Cancer immunoprevention

Immunoprevention is a fresh approach to cancer prevention based on the stimulation of the immune system before tumor onset. Immunoprevention was effective in various models of carcinogen-induced or autochthonous tumor progression. Vaccines made of cells or DNA plasmids combined with appropriate adjuvants completely blocked mammary carcinogenesis in HER-2/neu transgenic mice. At variance with cancer immunotherapy, the mediators of immunoprevention are antibodies and T-cell-derived cytokines, rather than cytotoxic T-cells. Immunopreventive approaches and chemoprevention with tamoxifen or cyclooxygenase-2 inhibitors can be combined advantageously. The success obtained in preclinical studies suggests that cancer immunoprevention should progress to clinical testing