Master developmental pathways like Notch, Wnt, and Hedgehog are signaling systems that control proliferation, cell death, motility, migration, and stemness. They are commonly activated in many solid tumors, where they drive or contribute to cancer initiation, but also primary and metastatic tumor development. The reactivation of developmental pathways in cancer stroma favors the development of cancer stem cells and allows their maintenance, pointing out these signaling pathways as particularly attractive targets for more efficient anticancer therapies, especially in advanced primary tumors and metastatic cancers. Metastasis, i.e., the colonization of distant organs by tumor cells from a primary site, is the worst feature of cancer development. It results from a cascade of events emerging from hijacking of epithelial–mesenchymal transition, angiogenesis, migration and invasion by transforming cells, and is associated with poor survival, drug resistance, and tumor relapse. In this chapter, we summarize and discuss experimental data suggesting pivotal roles for developmental pathways in cancer development and metastasis, considering the therapeutic potential. Emerging targeted antimetastatic therapies based on Notch, Wnt, and Hedgehog pathways are also discussed.

Multidrug-resistant bacteria constitute a major public health burden, as these lethal pathogens of fish, birds, and mammals cause difficult-to-treat health care–associated or community-acquired infections in humans. Indeed, recent information from the World Health Organization highlighted that drug-resistant infections already kill hundreds of thousands a year globally, and by 2050, that figure could be more than 10 million, with an associated economic burden of up to $100 trillion, if prompt actions are not taken. Staphylococcus aureus is a leading cause of fatal bacterial infections worldwide, with a death rate of about 20% of cases in industrialized countries (and even more in developing countries). Moreover, the economic implications of growing methicillin-resistant S. aureus (MRSA) incidence in community patients and farm animal lineages suggest that the burden of MRSA infections could even be more considerable than reported. This chapter endeavors to review the state of the knowledge of biological processes and signaling molecules accounting for the development of resistance in bacteria, with a particular emphasis on evidence from resistant and persistent variants of S. aureus .

Chronic myeloid leukemia (CML) is caused by the malignant transformation of hematopoietic stem cells in leukemic stem cells. From the introduction of the anti-cancer drug imatinib, the therapy of CML has been positively transformed. However, following treatment most patients display a residual CML disease attributed to the presence of quiescent leukemic stem cells intrinsically resistant to imatinib. Considering that the later cancer cells lose their chemoresistance in vitro, it appears that the stromal microenvironment plays a crucial role in CML-affected cell chemoresistance. In the present review, we summarize and discuss the recent findings on signaling pathways through which stromal cells sustain CML leukemogenesis, as well as leukemic stem cell maintenance and chemoresistance.

We have considered the possible effects of a diet containing genetically modified (GM) soybean on mouse testis. This organ, in fact, is a well known bioindicator and it has already been utilized, for instance, to monitor pollution by heavy metals. In this preliminary study, we have focussed our attention on Sertoli cells, spermatogonia and spermatocytes by means of immunoelectron microscopy. Our results point out that the immunolabelling for Sm antigen, hnRNPs, SC35 and RNA Polymerase II is decreased in 2 and 5 month-old GM-fed mice, and is restored to normal at 8 months. In GM-fed mice of all ages considered, the number of perichromatin granules is higher and the nuclear pore density lower. Moreover, we found enlargements in the smooth endoplasmic reticulum in GM-fed mice Sertoli cells. A possible role played by traces of the herbicide to which the soybean is resistant is discussed.

In eukaryotic cells, pre-mRNAs undergo several transformation steps to generate mature mRNAs. Recent studies have demonstrated that a diet containing a genetically modified (GM) soybean can induce modifications of nuclear constituents involved in RNA processing in some tissues of young, adult and old mice. On this basis, we have investigated the ultrastructural and immunocytochemical features of pre-implantation embryos from mice fed either GM or non- GM soybean in order to verify whether the parental diet can affect the morpho-functional development of the embryonic ribonucleoprotein structural constituents involved in pre-mRNA pathways. Morphological observations revealed that the general aspect of embryo nuclear components is similar in the two experimental groups. However, immunocytochemical and in situ hybridization results suggest a temporary decrease of pre-mRNA transcription and splicing in 2-cell embryos and a resumption in 4-8-cell embryos from mice fed GM soybean; moreover, pre-mRNA maturation seems to be less efficient in both 2-cell and 4-8-cell embryos from GM-fed mice than in controls. Although our results are still preliminary and limited to the pre-implantation phases, the results of this study encourage deepening on the effects of food components and/or contaminants on embryo development.

The aim of this paper is to review the data in the literature concerning ribonucleoprotein components during apoptosis, where a major rearrangement of RNPs takes place. In parallel with chromatin changes, the nucleoplasmic constituents (perichromatin fibrils; perichromatin granules; interchromatin granules and nuclear bodies) as well as the nucleoli aggregate into heterogeneous clusters called HERDS, in the interchromatin space. Later, these RNP-containing structures are extruded from the nucleus and leave the cell within cytoplasmic blebs. We propose also a role for HERDS as markers of irreversible transcriptional arrest.

Some opioid peptides are able to inhibit the growth of human prostatic cancer cells; in particular, the [D‐Ala2,D‐Leu5] enkephalin (DADLE) reduces PC3 cell growth. In order to understand how DADLE decreases cell proliferation, we investigated, by electron microscopy, its effects on PC3 cellular components. PC3 cells were incubated with DADLE and processed for both ultrastructural morphology and immunoelectron microscopy. Some cells were incubated with BrU to determine the transcriptional rate. BrU and DADLE molecules were detected by immunogold techniques and the labeling was quantitatively evaluated. Modifications of some cytoplasmic and nuclear components were observed in DADLE‐treated cells. Moreover, treated cells incorporated lower amounts of BrU than control cells. DADLE molecules were located in the cytoplasm and in the nucleus, especially on mRNA transcription and early splicing sites. Our data suggest that DADLE is able to slow down the synthetic activity of PC3 cells, perhaps interfering with nuclear functions. Microsc. Res. Tech. 64:243–249, 2004. © 2004 Wiley‐Liss, Inc.