L. M. Antón Aparicio

Cyclooxygenase-2 (COX-2): a molecular target in prostate cancer

Epidemiological studies provided the first evidence that COX may be involved in the pathogenesis of cancer. In the process of carcinogenesis and in the route of intracellular signalling during carcinogenesis, COX-2 expression may be a universal phenomenon. In general, COX-2 is up-regulated throughout the tumorigenic process, from early hyperplasia to metastatic disease. COX-2 has been reported to be constitutively overexpressed in a variety of malignancies and is frequently constitutively elevated in prostate carcinoma. COX-2 was consistently overexpressed in premalignant lesions such as prostatic intraepithelial neoplasia, and carcinoma. Cases are described with evolution of proliferative inflammatory atrophy of the prostate and prostate carcinoma. The increase of evidence implicating COX-2 in cancer has stimulated clinical trials to investigate the efficacy of selective COX-2 inhibitors in individuals at risk for human cancer. Regarding prostate carcinoma there is much direct or indirect evidence to support the use of COX-2 inhibitors in this disease. Trials using these drugs in familial adenomatous polyposis (FAP) and other patients with a high risk of colorectal carcinoma are ongoing.

Prostate cancer and Hedgehog signalling pathway.

The Hedgehog (Hh) family of intercellular signalling proteins have come to be recognised as key mediators in many fundamental processes in embryonic development. Their activities are central to the growth, patterning and morphogenesis of many different regions within the bodies of vertebrates. In some contexts, Hh signals act as morphogens in the dose-dependent induction of distinct cell fates within a target field, in others as mitogens in the regulation of cell proliferation or as inducing factors controlling the form of a developing organ. These diverse functions of Hh proteins raise many intriguing questions about their mode of action. Various studies have now demonstrated the function of Hh signalling in the control of cell proliferation, especially for stem cells and stem-like progenitors. Abnormal activation of the Hh pathway has been demonstrated in a variety of human tumours. Hh pathway activity in these tumours is required for cancer cell proliferation and tumour growth. Recent studies have uncovered the role for Hh signalling in advanced prostate cancer and demonstrated that autocrine signalling by tumour cells is required for proliferation, viability and invasive behaviour. Thus, Hh signalling represents a novel pathway in prostate cancer that offers opportunities for prognostic biomarker development, drug targeting and therapeutic response monitoring.

Fructose transporter GLUT5 expression in clear renal cell carcinoma.

Renal cell carcinomas (RCC) can be subclassified for general purposes into clear cell, papillary cell, chromophobe cell carcinomas and oncocytomas. Other tumours such as collecting duct, medullary, mucinous tubular and spindle cell and associated with Xp 11.2 translocations/TFE 3 gene fusion, are much less common. There is also a residual group of unclassified cases. Previous studies have shown that RCC has high glycolytic rates, and expresses GLUT transporters, but no distinction has been made among the different subtypes of renal cell tumours and their grades of malignancy. In clear renal cell carcinoma (cRCC) glycogen levels increase, glycolysis is activated and gluconeogenesis is reduced. The clear cell subtype of RCC is characterized histologically by a distinctive pale, glassy cytoplasm and this appearance of cRCC is due to abnormalities in carbohydrate and lipid metabolism, and this abnormality results in glycogen and sterol storage. Several isoforms of glucose carriers (GLUTs) have been identified. We show here in a panel of 80 cRCC samples a significant correlation between isoform 5 (GLUT5) and many pathological parameters such as grade of differentiation, pelvis invasion and breaking capsule. GLUT5 expression also appears to associate more strongly with the clear cell RCC subtype. These data suggest a role for the GLUT5 isoform in fructose uptake that takes place in cRCC cells and which subsequently leads to the malignant RCC progression.

Prostate carcinoma and stem cells

Stem cells, as classically defined, are cells with a capacity to self-renew and to generate daughter cells that can differentiate down several cell lineages to form all of the cell types that are found in the mature tissue. Stem cells and tumour cells have many similar features, including infinite lifespan, self-renewal, multidrug resistance, telomerase expression and, in the instance of the prostate, androgen independence. Evidence supports a role for stem cells in the etiology of many types of cancer. The evolution of androgen-independent prostate carcinoma may reflect the emergence of stemlike prostate tumour cells. Because cancer may be a disease of stem cell lineages and Shh-Gli signalling controls the behaviour of precursors and of cells with stem cell properties in the mammalian tissues, prostate cancer might derive from inappropriate expansion of prostatic epithelial stem cell lineages caused by abnormal Shh-Gli function. This review attempts to integrate these recent results.

Non-seminomatous germ-cell tumour associated with acute megakaryoblastic leukaemia

The association of mediastinal germ-cell tumours (MGCTs) with haematologic neoplasms is a rare though well known circumstance, and few cases are found in the literature. Most of these refer to non-seminomatous tumours in young males. The diagnosis of the haematological condition is usually either synchronic or metachronic with that of the germ-cell tumour. From those cases that have been published, we know that the prognosis is poor and basically determined by the haematologic neoplasia. The case report we present is that of a young male with an initial diagnosis of both conditions. It was possible to apply specific treatment, initially in the case of the leukaemia, and later in the case of the germ-cell tumour. The approach adopted is a multidisciplinary one.

Cytokine and endocrine signaling in prostate cancer

Prostate epithelial and stromal cells develop paracrine interactions, which may be responsible for the occurrence and progression of prostate pathologies. Strikingly, stromal cells exhibit pleiotropic effects on epithelial cell growth, ranging from stimulation to inhibition. Steroid hormone receptors are considered ligand-activated transcriptional factors. Moreover, it has been suggested that the human androgen receptor can also be activated in the absence of surrounding ligands such as growth factors and cytokines. Strong evidence suggests that cytokines may play an important role in ligand-independent activation of androgen receptor in prostate cancer cells. In our view, one of the most striking finding in the prostate cancer development process is the relationship between carcinogenesis and secretion of cytokines.

Role of taxanes in advanced prostate cancer

Advanced prostate cancer is an androgen-dependent disease for which the initial treatment is an androgen deprivation maneuver. However, some primary resistances to hormonal treatment occur with increasing incidence throughout the evolution of the disease. The taxanes, docetaxel and cabazitaxel, exert their action at multiple levels at the tumor cell: besides inhibiting the mitosis and inducing the cell death, they induce the nuclear accumulation of FOXO1, a potent nuclear factor that acts against the activation of androgen receptor inhibiting the transcription of AR-V7 variant associated with the development of resistances to abiraterone and enzalutamide. Docetaxel, as first-line therapy, and cabazitaxel, as second-line therapy, have demonstrated to increase the survival in castration-resistant prostate cancer. The results from last studies either on high-risk localized disease or on androgen-sensitive tumors demonstrate the increasing role of taxanes at earlier states of prostate cancer.

Choroid plexus carcinoma: a rare condition and its therapeutic management

Choroid plexus carcinomas are rare tumours, found chiefly during childhood. The commonest pattern of progression is via the neural axis. We present the case of a patient with unusual metastatic dissemination, affecting lungs and bones two years after diagnosis, and the approach adopted towards him.

Integrated analysis of mRNA and miRNA to unravel novel mechanisms of sunitinib long term response in mRCC.

e16080Background: Normal and pathological angiogenesis is under the control of various developmental genetic programs, including Notch and Hedgehog pathways. More recently, miRNAs have emerged as k...

New Therapeutic Strategies in Small Cell Lung Cancer: The Stem Cell Target

In 1889, Sir S. Paget introduced the soil and seed hypothesis of metastasis to medicine and credited the idea to Fuchs. In Paget s study, he concluded that the distribution of metastases cannot be due to chance alone and that different tissues provide optimal conditions for the growth of specific cancers. In the soil and seed metaphor, the soil refers to the secondary site of tumour growth and development and perhaps the chemical signals produced in the microenvironment at the sites of metastasis. The seed is the ostensible stem cell or tumourinitiating cell from the primary tumour. These tumour-initiating cells are the tumorigenic force behind tumour initiation, growth, metastasis, drug resistance, and relapse. In a variation of this idea, called the homing hypothesis, a secondary signal secreted by cells at the future metastatic sites “calls” the tumour cells to the site and permits them to proliferate in the new environment. In this hypothesis, the seed produces cell surface receptors that are able to recognise the site demarcated by the soil. Although the mechanisms that define tissue specificity remain obscure, researchers have focused on small messenger molecules as attractants and larger cell surface receptors that guide the tumour-initiating cells. Based on the hypothesis introduced by Paget, other groups have focused on chemokines and their receptors as viable candidates for soil and seed signalling and have proposed a “spatial and temporal code” composed of specific combinations of such molecules, while other molecules are responsible for neovascularisation, metastasis, and immunosurveillance avoidance. Lung cancers result from complex genetic and epigenetic changes and are characterised by stepwise malignant progression of cancer cells with an associated accumulation of genetic alterations. This process, referred to as multistep carcinogenesis, develops through the clonal evolution of initiated lung cells. Initiation consists of the acquisition of defined genetic alterations in a small number of genes that confer a proliferative advantage and facilitate progression towards invasive neoplasia. Although many of these genetic changes occur independently of histological type, their frequency and timing of occurrence with respect to cancer progression differ between small cell lung carcinomas (SCLC), which may originate from epithelial cells with neuroendocrine features, and non-SCLCs, which