Abstract CN08-03: Targeting Molecular Pathways in the Tumor Microenvironment: A holistic Approach for Cancer Chemoprevention

Tumor microenvironment (TME) is now considered an integral part of carcinogenesis, playing critical role in tumor growth, epithelial to mesenchymal transition (EMT), angiogenesis, invasion, migration and metastasis. Beside its vital role in carcinogenesis, TME is also regarded as a better drug target because of its relative genetic stability with lesser probability for drug-resistance development. TME, in general, defines the dynamic cellular and extra-cellular components surrounding tumor cells at each stage of carcinogenesis, encompassing several distinct cell types, including cancer-associated fibroblasts (CAFs), endothelial cells, pericytes, smooth muscle cells, neutrophils, macrophages, dendritic cells, natural killer cells, adipocytes, lymphocytes etc. Besides, TME is also enriched in non-cellular components such as cytokines, growth factors, hormones, and components of the extracellular matrix. TME is not to be regarded as a passive response towards transformed or growing tumor cells; instead, TME should be viewed as an equal and active contributing partner in cancer growth and progression. In several instances, TME not only determines whether the dysfunctional epithelial cells will continue to grow and invade in particular milieu but also governs whether they will become dormant or should regress and be removed. TME is therefore, an integrated and inseparable component of carcinogenesis. In light of its critical importance at every stage of carcinogenesis, there is an urgent need to identify and establish chemopreventive targets in the complex and heterogeneous TME along with the tumor. Accumulated pre-clinical, clinical and epidemiological evidence, also advocates the TME to be a prime target in any translational cancer chemoprevention strategy. In particular, cancer chemoprevention approaches should emphasize the identification and targeting of the molecular signatures specific to the TME, because a generalized targeting of the microenvironment might also adversely affect normal tissue homeostasis and lead to undesirable effects. We strongly believe that cancer chemopreventive strategies targeting both tumor and TME would be better and more effective towards preventing, retarding or reversing the process of carcinogenesis. In this regard, our completed and ongoing studies clearly show that the natural cancer chemopreventive agent ‘silibinin’, a flavonolignan isolated from the seeds of Silybum marianum, targets tumor growth, angiogenesis, EMT, invasion, migration and metastasis. In my presentation, today, I will elaborate on studies with major focus on the effects of silibinin on TME components and their interaction with cancer cells. Results from these studies are highly encouraging as silibinin was identified as targeting TME effectively and more importantly, at much lower concentrations compared to its inhibitory effect on cancer cells. Since, silibinin is already in clinical trials, and based upon the results of all the in vitro and in vivo studies, we recommend that its chemopreventive effectiveness should be verified through its effect on biological end points in both tumor and TME. Citation Format: Rajesh Agarwal. Targeting molecular pathways in the tumor microenvironment: A holistic approach for cancer chemoprevention. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr CN08-03.