Normal hepatocyte transplantation delays the emergence of chemically induced preneoplastic nodules in rat liver

Cancer often arises in a background of chronic tissue damage. It is also increasingly appreciated that such an injured tissue microenvironment might foster the selective emergence of altered cells, leading to neoplasia. Accordingly, reversal of chronic tissue damage could represent a potential strategy to counteract neoplastic disease. In these studies, we aim to investigate whether transplantation of normal cells in the context of an injured, neoplastic-prone microenvironment might impact on the evolution of the carcinogenic process. A rat model of chemically-induced hepatocarcinogenesis was used. Animals were given a single dose of diethylnitrosamine (DENA), followed by two injections of retrorsine (RS), a pyrrolizidine alkaloid that imposes a persistent block on hepatocyte cell cycle. At the end of this protocol, rats were either given no further treatment or injected, via the portal circulation, with 4 million normal hepatocytes isolated from a syngenic donor. A second group of animals was similarly exposed to DENA+RS protocol followed by transplantation of normal hepatocytes. After 3 months, rats given DENA+RS alone displayed numerous discrete nodular lesions (up to 30 per liver), ranging 1 to 3 mm in size. On the other hand, in animals receiving DENA+RS and transplantation, donor hepatocytes were able to repopulate over 50% host liver, as expected. Most importantly, both the number and the size of hepatocyte nodules were greatly reduced in these animals (percent nodular area was 1.8±0.3, down from a control value of 8.5±2.8). The above data indicate that strategies aimed at re-establishing a normal tissue microenvironment might be relevant to the management of neoplastic disease

The growth pattern of transplanted normal and nodular hepatocytes

Overt neoplasia is often the end result of a long biological process beginning with the appearance of focal lesions of altered tissue morphology. While the putative clonal nature of focal lesions has often been emphasized, increasing attention is being devoted to the possible role of an altered growth pattern in the evolution of carcinogenesis. Here we compare the growth patterns of normal and nodular hepatocytes in a transplantation system that allows their selective clonal proliferation in vivo. Rats were pre-treated with retrorsine, which blocks the growth of resident hepatocytes, and were then transplanted with hepatocytes isolated from either normal liver or hepatocyte nodules. Both cell types were able to proliferate extensively in the recipient liver, as expected. However, their growth pattern was remarkably different. Clusters of normal hepatocytes integrated in the host liver, displaying a normal histology; however, transplanted nodular hepatocytes formed new hepatocyte nodules, with altered morphology and sharp demarcation from surrounding host liver. Both the expression and distribution of proteins involved in cell polarity, cell communication, and cell adhesion, including connexin 32, E-cadherin, and matrix metalloproteinase-2, were altered in clusters of nodular hepatocytes. Furthermore, we were able to show that down-regulation of connexin 32 and E-cadherin in nodular hepatocyte clusters was independent of growth rate. These results support the concept that a dominant pathway towards neoplastic disease in several organs involves defect(s) in tissue pattern formation

Cancer Biomarker Discovery: The Entropic Hallmark

Background: It is a commonly accepted belief that cancer cells modify their transcriptional state during the progression of the disease. We propose that the progression of cancer cells towards malignant phenotypes can be efficiently tracked using high-throughput technologies that follow the gradual changes observed in the gene expression profiles by employing Shannon's mathematical theory of communication. Methods based on Information Theory can then quantify the divergence of cancer cells' transcriptional profiles from those of normally appearing cells of the originating tissues. The relevance of the proposed methods can be evaluated using microarray datasets available in the public domain but the method is in principle applicable to other high-throughput methods. Methodology/Principal Findings: Using melanoma and prostate cancer datasets we illustrate how it is possible to employ Shannon Entropy and the Jensen-Shannon divergence to trace the transcriptional changes progression of the disease. We establish how the variations of these two measures correlate with established biomarkers of cancer progression. The Information Theory measures allow us to identify novel biomarkers for both progressive and relatively more sudden transcriptional changes leading to malignant phenotypes. At the same time, the methodology was able to validate a large number of genes and processes that seem to be implicated in the progression of melanoma and prostate cancer. Conclusions/Significance: We thus present a quantitative guiding rule, a new unifying hallmark of cancer: the cancer cell's transcriptome changes lead to measurable observed transitions of Normalized Shannon Entropy values (as measured by high-throughput technologies). At the same time, tumor cells increment their divergence from the normal tissue profile increasing their disorder via creation of states that we might not directly measure. This unifying hallmark allows, via the the Jensen-Shannon divergence, to identify the arrow of time of the processes from the gene expression profiles, and helps to map the phenotypical and molecular hallmarks of specific cancer subtypes. The deep mathematical basis of the approach allows us to suggest that this principle is, hopefully, of general applicability for other diseases

Liver repopulation and carcinogenesis: two sides of the same coin?

Liver repopulation by transplanted normal hepatocytes has been described in a number of experimental settings. Extensive repopulation can also occur from the selective proliferation of endogenous normal hepatocytes, both in experimental animals and in the human liver. This review highlights the intriguing association between clinical and experimental conditions related to liver repopulation and an increased risk for development of hepatocellular carcinoma. It is suggested that any microenvironment that is able to sustain the clonal growth of normal transplanted (or endogenous) hepatocytes is also geared to select for the emergence of rare resistant cells with an altered phenotype. Whereas the first pathway leads to liver repopulation with normal histology, the latter results in the growth of focal proliferative lesions and carries an increased risk of neoplastic disease. The implications of this association are discussed, both in terms of pathogenetic significance and possible therapeutic exploitation

Ultrasonographic study of Peyronie's disease

Induratio penis plastica (IPP) is a degenerative disease, which consists in a thickening of the albuginea tunica of cavernous corpora, especially on the dorsal aspect. In 25% of the cases a calcified deposit is present. This disease can determine a bending of the penis, usually upward, pain during erection and impotentia coeundi. It is associated with Dupuytren's disease in 25% of the cases. IPP is of unknown etiological origin. The more reliable etiological theories are the degenerative one (micro trauma and inflammation) and the autoimmune one. The assessment of IPP is based on story, physical examination, autophotography (which are necessary) and on imaging techniques such as ultrasound, color Doppler, CT, MRI and X-ray in mammography. Color Doppler has demonstrated to be the best technique because of its cost/benefit and cost/effectiveness ratio. RMI with gadolinium can determine plaques activity but it has a lower cost/benefit ratio. Color Doppler can determine the presence of an IPP plaque and its status, which is size, location, and degree of calcification. Some authors sustain that inflammation can be suggested by the presence of micro vascularization around the plaque. US can be very useful to detect plaque in a size not easily accessible by physical examination (on the dorsal aspect of the penis) and to demonstrate plaques in different evolution moment. Ultrasonography is the better technique to show directly albuginea tunica. Authors illustrate the methodology, which use intra-cavernous injection of prostaglandin E1 (PGE1) to induce erection and its semeiotic findings

Cancer as a disease of tissue pattern formation

The diagnosis of neoplastic disease still lays its foundations on the detection of altered tissue morphology. Most importantly, cancer begins, at least in many cases as a disease with altered tissue pattern formation. It is therefore rather surprising that the issue regarding the possible mechanistic role of such property in the pathogenesis of cancer has received relatively little attention so far. To be more specific, we need to ask the following question: is altered tissue pattern formation a mere bystander, with its pervasive presence along the entire carcinogenic sequence, or does it play a role in fuelling this process? Pathways related to morphogenesis and to the establishment of cell polarity will be considered for their possible mechanistic involvement in early phases of neoplastic disease. Evidences and hypotheses relating altered tissue pattern formation to the emergence of the tumor microenvironment and to neoplastic progression will be discussed