Search

Metalloproteinases (MMPs) are a cluster of at least 23 enzymes belonging to the more wide family of endopeptidases called Metzincins, whose structure is characterized by the presence of a zinc ion at the catalytic site. Although the general view of MMPs as physiologic scissors involved in extracellular matrix (ECM) degradation and tissue remodeling is still valid, additional functions have recently emerged, including the ability to cleave non ECM molecules such as growth factors, cytokines and chemokines from their membrane-anchored proforms. These functions are utilized by tumor cells and are fundamental in the determination of tumor progression and invasion. The effect of MMPs activity in cancer progression has been traditionally associated with the acquisition by tumor cells of an invasive phenotype, an indispensable requisite for the metastatic spreading of cancer cells. In addition to the traditional view, a new role for MMPs in creating a favourable microenvironment has been proposed, so that MMPs are not only involved in cell invasion, but also in signaling pathways that control cell growth, inflammation, or angiogenesis. Finally, recent evidence suggest a role of MMPs in the so called “pre-metastatic niche” that is the hypothesis of an early distant modification of the premetastatic site by primary cancer cells. This new hypothesis is changing our traditional view about MMPs and provides important insights into the effective time window for the therapeutic use of MMP inhibitors. In this review we provide the main available data about the ability of MMPs in creating a suitable microenvironment for tumor growth in metastatic sites and we indicate the implication of these data on the potential use of MMP inhibitors in the metastatic therapy.

Bone metastases contribute to morbidity in patients with common cancers, and conventional therapy provides only palliation and can induce systemic side effects. The development of nanostructured delivery systems that combine carriers with bone-targeting molecules can potentially overcome the drawbacks presented by conventional approaches. We have recently developed biodegradable, biocompatible nanoparticles (NP) made of a conjugate between poly (D,Llactide- co-glycolic) acid and alendronate, suitable for systemic administration, and directly targeting the site of tumorinduced osteolysis. Here, we loaded NP with doxorubicin (DXR), and analyzed the in vitro and in vivo activity of the drug encapsulated in the carrier system. After confirming the intracellular uptake of DXR-loaded NP, we evaluated the antitumor effects in a panel of human cell lines, representative for primary or metastatic bone tumors, and in an orthotopic mouse model of breast cancer bone metastases. In vitro, both free DXR and DXR-loaded NP, (58-580 ng/mL) determined a significant dose-dependent growth inhibition of all cell lines. Similarly, both DXR-loaded NP and free DXR reduced the incidence of metastases in mice. Unloaded NP were ineffective, although both DXR-loaded and unloaded NP significantly reduced the osteoclast number at the tumor site (P 0.014, P 0.040, respectively), possibly as a consequence of alendronate activity. In summary, NP may act effectively as a delivery system of anticancer drugs to the bone, and deserve further evaluation for the treatment of bone tumors.

Experimental prostate cancer bone metastases are difficult to form in vivo, and some typical clinical patterns remain irreproducible. In our work we describe new metastatic models in vivo using different experimental approaches.Methods We injected prostate cancer cells in the left cardiac ventricle or in the medullar cavity of tibia of male nude mice.Results Mice were monitored by x-ray analysis and 70% of them revealed osteolytic lesions 40 days after heart injection. By scintigraphy and alu-PCR we were able to identify early a higher number of metastatic loci than by x-ray.Conclusions Heart and intratibial injection of prostate cancer cells in nude mice may represent a good experimental model to investigate the pathophysiology of bone and bone marrow metastases in vivo.

The aim of this study was to investigate the regional expression of thyroid hormone nuclear receptor forms (TRαand TRβ) and isoform (TRα1and TRβ2) mRNAs in normal and neoplastic (benignant and malignant) human thyroid tissue. Tumor specimens from patients with thyroid carcinomas (papillary: 5 cases; follicular: 5 cases; anaplastic: 2 cases), thyroid follicular adenomas (7 cases) and tissue from normal thyroid glands (12 cases) were analyzed by in situhybridization and semiquantitative RT-PCR for the expression of TRα1and β, as well as for the isoform α2that does not bind the hormone. In normal tissues, TRα2was expressed at lower levels compared to TRα1(α1/α2=4.3). In papillary and follicular carcinomas, the expression of TRα1and TRβdid not change as compared with normal thyroid tissue and adenomas (0.87±0.15 SD vs 0.89±0.17 den-sitometric units, DU, and 0.15±0.02 vs 0.14±0.03 DU, respectively). However, the expression of TRα2was significantly higher in differentiated carcinomas compared to normal thyroid tissue and adenomas (0.47±0.05 vs 0.20±0.05 DU, p<0.05) with α1/α2=1.4. In anaplastic carcinoma all TRs were absent. We concluded that both normal and pathological thyroid tissues, with the exception of anaplastic carcinoma, express all TRs in thyreocites and that differentiated thyroid carcinomas are associated in enhancing the expression of TRα2mRNA.

High affinity-low capacity nuclear triiodothyronine (T3) receptors (TRs), identified as a product of c-erbAaproto-oncogene, are expressed in prepubertal rat Sertoli cell. At this age, exogenous T3treatment as well as hypothyroidism affects Sertoli cell functions. We examined the ontogenetic expression pattern of TRs in the rat testis. Northern analysis confirms that TRsare expressed at high level from fetal development until prepubertal period. Rnase protection analysis demonstrates that TRa2, the variant isoform of TRa1, is constitutively expressed at all ages, while TRa3is absent in the adult gonad. While TRa1and TRa2expression declines during development, Rev-erbAa(Rev), the antisense mRNA encoded by the same c-erbAagenomic locus, increases beginning 5 days after birth and maximizing in adulthood. TRa1, TRa2, and Rev mRNAsdo not appear to be directly regulated by thyroid hormone in testis; however, short-term neonatal hypothyroidism leads to the expression of TRa1and its variant in adult testis, which is absent in control coeval animals. Thus, during development of rat testis, the levels of messages of genes encoded in the c-erbAagenomic locus have different ontogenetic control. The ontogenetic profile of TRa1and its variant isoforms within the seminiferous epithelium suggests that these receptors are involved in the differentiation of the male gonad.

The expression of epidermal growth factor receptor (EGFR) is a distinctive marker in the biologic progression of prostatic carcinoma (PCa). Gefitinib (‘Iressa’) is an orally active EGFR tyrosine kinase inhibitor, and in clinical trials has shown important antitumor activity in tumors expressing EGFR. Our aim was to demonstrate that Gefitinib was also effective in inhibiting the cellular capabilities leading to metastasis formation.Methods The inhibitory effect of Gefitinib on the invasive phenotype of PCa cells was tested in vivo by injecting PC3 cells subcutaneously (Xenograft) or into the left ventricle of nude mice and by daily administration of various doses of Gefitinib.Results The tumoral growth of xenograft was significantly inhibited by 150mg/kg Gefitinib with a reduction of 40% in tumor weight. Moreover mice receiving tumoral cells intracardially showed a significant reduction in bone metastases when treated with Gefitinib.Conclusions Our data demonstrate that EGF is able to sustain not only cellular growth, but also metastatic progression. For this reason the use of Gefitinib as a therapeutic agent may also be indicated in the control of tumor spreading in EGF responsive tumor cells.