Principles of Modular Tumor Therapy

Nature is interwoven with communication and is represented and reproduced through communication acts. The central question is how may multimodal modularly acting and less toxic therapy approaches, defined as modular therapies, induce an objective response or even a continuous complete remission, although single stimulatory or inhibitingly acting drugs neither exert mono-activity in the respective metastatic tumor type nor are they directed to potentially ‘tumor-specific’ targets. Modularity in the present context is a formal pragmatic communicative systems concept, describing the degree to which systems objects (cells, pathways etc.) may be communicatively separated in a virtual continuum, and recombined and rededicated to alter validity and denotation of communication processes in the tumor. Intentional knowledge, discharging in reductionist therapies, disregards the risk-absorbing background knowledge of the tumor’s living world including the holistic communication processes, which we rely on in every therapy. At first, this knowledge constitutes the validity of informative intercellular processes, which is the prerequisite for therapeutic success. All communication-relevant steps, such as intentions, understandings, and the appreciation of messages, may be modulated simultaneously, even with a high grade of specificity. Thus, modular therapy approaches including risk-absorbing and validity-modifying background knowledge may overcome reductionist idealizations. Modular therapies show modular events assembled by the tumor’s living world as an additional evolution-constituting dimension. This way, modular knowledge may be acquired from the environment, either incidentally or constitutionally. The new communicatively defined modular coherency of environment, i.e. the tumor-associated microenvironment, and tumor cells open novel ways for the scientific community in ‘translational medicine’

Diclofenac Inhibits Tumor Growth in a Murine Model of Pancreatic Cancer by Modulation of VEGF Levels and Arginase Activity

BACKGROUND: Diclofenac is one of the oldest anti-inflammatory drugs in use. In addition to its inhibition of cyclooxygenases (COX), diclofenac potently inhibits phospholipase A(2) (PLA(2)), thus yielding a broad anti-inflammatory effect. Since inflammation is an important factor in the development of pancreatic tumors we explored the potential of diclofenac to inhibit tumor growth in mice inoculated with PANCO2 cells orthotopically. METHODOLOGY/PRINCIPAL FINDINGS: We found that diclofenac treatment (30 mg/kg/bw for 11 days) of mice inoculated with PANC02 cells, reduced the tumor weight by 60%, correlating with increased apoptosis of tumor cells. Since this effect was not observed in vitro on cultured PANCO2 cells, we theorized that diclofenac beneficial treatment involved other mediators present in vivo. Indeed, diclofenac drastically decreased tumor vascularization by downregulating VEGF in the tumor and in abdominal cavity fluid. Furthermore, diclofenac directly inhibited vascular sprouting ex vivo. Surprisingly, in contrast to other COX-2 inhibitors, diclofenac increased arginase activity/arginase 1 protein content in tumor stroma cells, peritoneal macrophages and white blood cells by 2.4, 4.8 and 2 fold, respectively. We propose that the subsequent arginine depletion and decrease in NO levels, both in serum and peritoneal cavity, adds to tumor growth inhibition by malnourishment and poor vasculature development. CONCLUSION/SIGNIFICANCE: In conclusion, diclofenac shows pronounced antitumoral properties in pancreatic cancer model that can contribute to further treatment development. The ability of diclofenac to induce arginase activity in tumor stroma, peritoneal macrophages and white blood cells provides a tool to study a controversial issue of pro-and antitumoral effects of arginine depletion

Identification of Prognostic Molecular Features in the Reactive Stroma of Human Breast and Prostate Cancer

Primary tumor growth induces host tissue responses that are believed to support and promote tumor progression. Identification of the molecular characteristics of the tumor microenvironment and elucidation of its crosstalk with tumor cells may therefore be crucial for improving our understanding of the processes implicated in cancer progression, identifying potential therapeutic targets, and uncovering stromal gene expression signatures that may predict clinical outcome. A key issue to resolve, therefore, is whether the stromal response to tumor growth is largely a generic phenomenon, irrespective of the tumor type or whether the response reflects tumor-specific properties. To address similarity or distinction of stromal gene expression changes during cancer progression, oligonucleotide-based Affymetrix microarray technology was used to compare the transcriptomes of laser-microdissected stromal cells derived from invasive human breast and prostate carcinoma. Invasive breast and prostate cancer-associated stroma was observed to display distinct transcriptomes, with a limited number of shared genes. Interestingly, both breast and prostate tumor-specific dysregulated stromal genes were observed to cluster breast and prostate cancer patients, respectively, into two distinct groups with statistically different clinical outcomes. By contrast, a gene signature that was common to the reactive stroma of both tumor types did not have survival predictive value. Univariate Cox analysis identified genes whose expression level was most strongly associated with patient survival. Taken together, these observations suggest that the tumor microenvironment displays distinct features according to the tumor type that provides survival-predictive value

Benign mammary epithelial cells enhance the transformed phenotype of human breast cancer cells

<p>Abstract</p> <p>Background</p> <p>Recent research has yielded a wealth of data underscoring the key role of the cancer microenvironment, especially immune and stromal cells, in the progression of cancer and the development of metastases. However, the role of adjacent benign epithelial cells, which provide initial cell-cell contacts with cancer cells, in tumor progression has not been thoroughly examined. In this report we addressed the question whether benign MECs alter the transformed phenotype of human breast cancer cells.</p> <p>Methods</p> <p>We used both <it>in vitro </it>and <it>in vivo </it>co-cultivation approaches, whereby we mixed GFP-tagged MCF-10A cells (G2B-10A), as a model of benign mammary epithelial cells (MECs), and RFP-tagged MDA-MB-231-TIAS cells (R2-T1AS), as a model of breast cancer cells.</p> <p>Results</p> <p>The <it>in vitro </it>studies showed that G2B-10A cells increase the colony formation of R2-T1AS cells in both soft agar and clonogenicity assays. Conditioned media derived from G2B-10A cells enhanced colony formation of R2-T1AS cells, whereas prior paraformaldehyde (PFA) fixation of G2B-10A cells abrogated this enhancement effect. Moreover, two other models of benign MECs, MCF-12A and HuMECs, also enhanced R2-T1AS colony growth in soft agar and clonogenicity assays. These data reveal that factors secreted by benign MECs are responsible for the observed enhancement of the R2-T1AS transformed phenotype. To determine whether G2B-10A cells enhance the tumorigenic growth of co-injected R2-T1AS cells <it>in vivo</it>, we used the nude mouse xenograft assay. Co-injecting R2-T1AS cells with G2B-10A cells ± PFA-fixation, revealed that G2B-10A cells promoted a ~3-fold increase in tumor growth, irrespective of PFA pre-treatment. These results indicate that soluble factors secreted by G2B-10A cells play a less important role in promoting R2-T1AS tumorigenesis <it>in vivo</it>, and that additional components are operative in the nude mouse xenograft assay. Finally, using array analysis, we found that both live and PFA-fixed G2B-10A cells induced R2-T1AS cells to secrete specific cytokines (IL-6 and GM-CSF), suggesting that cell-cell contact activates R2-T1AS cells.</p> <p>Conclusions</p> <p>Taken together, these data shift our understanding of adjacent benign epithelial cells in the cancer process, from passive, noncontributory cells to an active and tumor-promoting vicinal cell population that may have significant effects early, when benign cells outnumber malignant cells.</p

4980: Myeloid cells display immunosuppression activities during pregnancy, participating to the establishment of pre-metastatic niches

During pregnancy, major physiological changes occur that include inflammation and reduced immunity, conditions that are both implicated in promoting tumor growth. Tumors are indeed more aggressive during pregnancy and have greater metastatic proclivity. To gain insight into the mechanisms that may render pregnancy permissive for tumor growth, we addressed the biological and functional properties of myeloid-derived suppressor cells (MDSC), a heterogeneous population of hematopoietic cells of variable plasticity and immunoregulatory properties, during mouse and human gestation. Gene expression profiling of mouse MDSC has been shown to differ in pregnant and virgin mice, and the gene expression profile of pregnant animal-derived MDSC bears similarity to that observed in MDSC of tumor bearing mice. Common induced genes include Fibronectin1 and Olfactomedin4, which are known to be involved in extracellular matrix remodeling and tissue permissiveness to tumor cell implantation. In human pregnancy, CD33+ myeloid cells isolated from peripheral blood mononuclear cells (PBMC) are shown to be more strongly inhibitory of T cell proliferation in pregnant than in non-pregnant women. We also observed reduced natural killer cell numbers in the circulation of pregnant women, but which was not linked to a decrease in their cytotoxic activity, even after co-culture with CD33+ PBMC. Our observations suggest that mouse MDSC, as well as human CD33+ cell populations that arise during the physiological state of gestation, mimic tumor progression-associated MDSC and participate in the constitution of a permissive soil, often referred to as the pre-metastatic niche