BBA - Reviews on Cancer (v.1705, #2)

The role of gelatinases in colorectal cancer progression and metastasis by Olaf R.F. Mook; Wilma M. Frederiks; Cornelis J.F. Van Noorden (69-89).
Various proteases are involved in cancer progression and metastasis. In particular, gelatinases, matrix metalloproteinase-2 (MMP-2) and MMP-9, have been implicated to play a role in colon cancer progression and metastasis in animal models and patients. In the present review, the clinical relevance and the prognostic value of messenger ribonucleic acid (mRNA) and protein expression and proenzyme activation of MMP-2 and MMP-9 are evaluated in relation to colorectal cancer. Expression of tissue inhibitors of MMPs (TIMPs) in relation with MMP expression in cancer tissues and the relevance of detection of plasma or serum levels of MMP-2 and/or MMP-9 and TIMPs for prognosis are also discussed. Furthermore, involvement of MMP-2 and MMP-9 in experimental models of colorectal cancer is reviewed. In vitro studies have suggested that gelatinase is expressed in cancer cells but animal models indicated that gelatinase expression in non-cancer cells in tumors contributes to cancer progression. In fact, interactions between cancer cells and host tissues have been shown to modulate gelatinase expression in host cells. Inhibition of gelatinases by synthetic MMP inhibitors has been considered to be an attractive approach to block cancer progression. However, despite promising results in animal models, clinical trials with MMP inhibitors have been disappointing so far. To obtain more insight in the (patho)physiological functions of gelatinases, regulation of MMP-2 and MMP-9 expression is discussed. Mitogen activated protein kinase (MAPK) signalling has been shown to be involved in regulation of gelatinase expression in both cancer cells and non-cancer cells. Expression can be triggered by a variety of stimuli including growth factors, cytokines and extracellular matrix (ECM) components. On the other hand, MMP-2 and MMP-9 activity regulates bioavailability and activity of growth factors and cytokines, affects the immune response and is involved in angiogenesis. Because of the multifunctionality of gelatinases, it is unpredictable at what stage of cancer development and in which processes gelatinase activity is involved. Therefore, it is concluded that the use of MMP inhibitors to treat cancer should be considered carefully.
Keywords: Gelatinase; Colorectal cancer; Tumor progression; Metastasis; Clinical; Experimental model;

Measuring tumor pharmacodynamic response using PET proliferation probes: the case for 2-[11C]-thymidine by Paula Wells; Catharine West; Terry Jones; Adrian Harris; Pat Price (91-102).
[18F]-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) is becoming accepted as a diagnostic tool for cancer, but the potential uses of PET in oncology extend beyond the imaging of glucose metabolism. The development of a PET proliferation probe would be a useful pharmacodynamic tool. [11C]-thymidine PET has been assessed in man as a specific measure of tumor proliferation. Uptake of [11C]-thymidine is related to DNA synthesis and, in human tumors, correlates with proliferation. When compared with 18F-FDG, it has been shown to be a more sensitive discriminator of early clinical tumor response. 2-[11C]-thymidine PET scanning of patients enrolled in early phase clinical trials is feasible and should support future drug development. Although recent research is moving away from the validation of thymidine towards thymidine analogues radiolabeled with 18F, the better specificity of thymidine for DNA should be the rationale for its continued development and application as a PET probe.This review describes the historical development, application and current research status of [11C]-thymidine PET, and aims to highlight the need for its continuing development as a marker of tumor proliferation.
Keywords: Tumor; Positron emission tomography; 2-[11C]-Thymidine;

Meta-analysis of the role of p53 status in isogenic systems tested for sensitivity to cytotoxic antineoplastic drugs by Guido Cimoli; Davide Malacarne; Raffaella Ponassi; Monica Valenti; Saverio Alberti; Silvio Parodi (103-120).
The role of p53 in modifying sensitivity to cytotoxic drugs has been commonly studied by creating transfection pairs of wt p53 parental cells and altered p53 daughter cells, or vice versa. Authors inevitably tended to extrapolate and generalize their experimental observations, and conflicting reports have been more the rule than the exception. We have performed a meta-analysis of 356 independent studies. Average changes of drug sensitivity after a change of p53 status were observed. E6 transfection predominantly induces sensitization to cytotoxic drugs, whereas p53−/− knockout cells are more drug-resistant than their normal p53+/+ counterpart. Unexpectedly, transfection with a mutated p53 does not change much the drug sensitivity of most wt p53 cancer lines, with the notable exception of A2780, a predominant cell line in the studies analyzed (A2780 cells show increased resistance after transfection with a mutated p53). Rather interestingly, mitotic spindle poisons acted differently from other classes of cytotoxic drugs. A crucial indication of our findings is that the role of p53 alone in determining sensitivity/resistance to cytotoxic drugs is limited: the individual molecular pathology and differentiation of a given cancer line prevail over any average trend, and are causal to a broad spreading of the data. We also identify major “confounding factors”, alias independent categorical variables, capable of affecting the average outcome.
Keywords: p53 status; Isogenic system; Drug sensitivity;

Rho GTPases in human cancer: an unresolved link to upstream and downstream transcriptional regulation by Salvador A. Benitah; Pilar F. Valerón; Linda van Aelst; Christopher J. Marshall; Juan Carlos Lacal (121-132).
The high incidence of overexpression of some members of the Rho family of GTPases in human tumors suggests that (1) these proteins are involved in cancer onset, and (2) they are potential candidates for a therapeutic intervention. In recent years, the characterization of downstream effectors to Rho GTPases has provided crucial clues on the general cellular effects that permit aberrant proliferation and adhesiveness of tumor cells. The activation of many of these effector proteins in turn results in the modulation of the activity of several transcription factors that play an important role at various levels of Rho signaling. The precise mechanisms by which Rho GTPases participate in carcinogenesis are still not fully understood. However, it is becoming more evident that the specific role of Rho overexpression in tumor initiation, progression and metastasis, as well as the nature and cause of such overexpression in specific human tumors (i.e., transient or stable; tumor environment-regulated; genetic or epigenetic) may be linked to the activation of specific signaling pathways that result in transcriptional regulation. In this review, we summarize the functions of Rho proteins in the regulation of several transcription factors and their relationship to tumor biology.
Keywords: Rho GTPase; Transcription factor; Carcinogenesis;