CCBIO on Tumor Microenvironment (2015)
Cancer is a leading cause of death worldwide and a major health challenge; over half of current adults under the age of 65 years will be diagnosed with cancer at some point in their lifetime. Encouragingly, our understanding of the molecular basis of cancer has evolved remarkably during the past two decades.
Main content
The Cancer Genome Atlas (TCGA)聽program, following on the coattails聽of the Human Genome Project, has聽sequenced thousands of cancer cell聽genomes. TCGA has identified a broad聽range of recurrent gene mutations and聽genomic rearrangements that contribute聽to tumorigenesis. In concert with this, the聽pharmaceutical industry, following the聽success of imatinib (a small molecule聽targeting the BCR-ABL protein) for聽chronic myeloid leukemia (CML), and聽erlotinib (an EGF receptor inhibitor) for聽non-small cell lung cancer (NSCLC), has聽developed scores of molecularly targeted聽therapeutics, including many against聽specific protein mutations. In spite of聽this remarkable progress, most cancer聽patients still do not experience durable聽clinical responses, due to acquired drug聽resistance and subsequent relapse; and聽the War on Cancer continues.
The confounding reality for cancer聽treatment is the heterogeneity of聽tumors. This is a reflection not only of聽the intrinsic genetic instability of tumors聽but also of the extrinsic selective forces聽acting on an evolving tumor cell. The聽breakdown of normal tissue structure聽during malignant progression exposes聽tumor cells to numerous biophysical聽challenges, nutritional deprivation and聽a hostile non-native microenvironment聽comprising different matrix proteins and聽a variety of stromal cells. Philosophers聽refer to a confrontation that causes us to聽become aware of our own weaknesses as聽a 鈥渂oundary situation鈥�. A key outcome聽of the boundary situation is a realization聽of the necessity to communicate. Indeed,聽tumor cells that encounter a reactive聽stroma engage in reciprocal interactions聽that trigger adaptive, cellular plasticity聽related to stem cell differentiation and聽transdifferentiation, characteristic of聽adult tissue homeostasis and repair. This聽endows tumor cells with a remarkable聽phenotypic and functional flexibility, as聽evidenced by tumor vascular mimicry,聽epithelial-to-mesenchymal transition,聽and acquired drug resistance. This ability聽to assume different phenotypic states聽(鈥渟hape-shifting鈥�) allows adaptation to聽different niches within a dynamic tumor聽microenvironment. This new 鈥渉allmark鈥澛爋f cancer, tumor cell plasticity, is central聽to cancer progression and treatment failure.聽Indeed, tumor cell plasticity represents聽a unifying theme, reconciling different聽models of carcinogenesis (i.e. stochastic聽vs hierarchical) and is an important target聽for future cancer therapeutic development.
With the knowledge that an entire human聽being is derived from a single genome,聽we shouldn鈥檛 be surprised that multigenomic聽tumors are phenotypically聽diverse. Hence, deeper mechanistic聽insight into how the interaction between聽extrinsic microenvironmental and聽intrinsic genomic factors activates聽phenotypic plasticity programs in tumor聽cells is required to understand the聽tumor heterogeneity that undermines聽current treatments and to develop new聽therapeutic concepts to treat cancer. The聽investigators at CCBIO endeavor to聽better understand the molecular basis聽of tumor-stroma interactions that can聽inform improved treatment decisions聽and new therapeutic concepts.
Text: James B. Lorens
