State of the art research – University of Copenhagen

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State of the art research

Cancer is a major clinical problem in the EU, where it is responsible for about 25% of all deaths. Despite in increasing knowledge on cancer biology, few cancer cell targeting drugs have been successfully developed to date.

This is mainly due to the genetic heterogeneity of cancers and their ability to escape treatment by undergoing further mutations.

An alternative strategy is to inhibit tumor growth by targeting the tumor stroma, which consists of blood vessels, immune cells and fibroblasts. The important role of the tumor stroma was recently highlighted by the description of stroma gene expression profiles predicting breast cancer prognosis and drug response (5,6). Fibroblasts reside in every tissue of the body, but have a dynamically changing plasticity.

Accumulating evidence suggests that fibroblasts in various tissues are different and that even within each tissue type, a broad range of fibroblast heterogeneity exists. Cancer associated fibroblasts (CAFs), which in contrast to normal fibroblasts support cancer progression, arise by tumor‐induced activation of precursor cells such as endogenous tissue fibroblasts and adult tissue stem cells, and probably also bone marrow-derived mesenchymal stem cells (See the figur).

Given the heterogenous nature of normal tissue fibroblasts, combined with tissue specific mechanisms for CAF recruitment, different subsets of CAFs with different molecular signatures and functional properties will exist in a specific cancer and different cancers have different CAF subtypes.

CAFs are induced by cancer cells, but affect in a positive feedback-loop growth, survival and migration of tumor cells by secretion of growth factors, cytokines, extracellular matrix (ECM) proteins and ECM modifying metalloproteinases (See the figur).

Similarly, CAFs affect endothelial cells promoting angiogenesis, and recruit immune cells and bone marrow derived cells, which in turn can produce tumor--‐promoting factors. Furthermore, CAFs can affect cancer stem cell renewal, preconditioning of the metastatic niche, induce cancer cell EMT, and act as a “fuel” source of pyruvate for adjacent tumor cell growth.

CAFs seem to indirectly promote invasion of certain cancer cells by “drilling holes” through the ECM, through which the tumor cells migrate. Finally, elegant studies in mouse models of breast cancer have implicated CAF-regulated tumor stroma stiffness as a central actor in controlling tumor growth (8,9). While no consensus exists on the occurrence of mutations in CAFs, epigenetic changes appear to be crucial for the stable maintenance of the CAF phenotype. Since increased CAF numbers correlate with bad prognosis in colon, breast, pancreas and prostate cancer, CAFs are believed to play a crucial role in cancer progression in patients (1,6).

In the past 10 years the importance of the tumor microenvironment for tumor growth has received increasing recognition. More and more data point to a central role of the CAFs in tumor biology. Although the tumor promoting function of CAFs is widely accepted, our poor knowledge of the identity of CAF subpopulations and their molecular mode of action prohibit an effective development of cancer therapies targeting CAFs. Apparently, CAFs can activate quite a number of different tumor promoting pathways, but they seem to be not equally important in different cancers.

More information in this field will direct drug targeting to the prevention or elimination of the most dangerous CAF "subtypes" and the most harmful cancer promoting effector mechanisms. The many facets of CAF biology and their effector pathways makes it impossible for a single research group to address all relevant questions, as it demands intense international collaboration to achieve a critical mass of expertise, such as presented in our proposal.