Research in the Gullberg Lab

The Gullberg laboratory has characterized the integrin α11β1, which is expressed on subsets of normal fibroblasts and on carcinoma-associated fibroblasts. Cells lacking α11β1 display disturbed cell-collagen interactions, altered metalloproteinase synthesis and reduced cell proliferation. Major projects within the group aim to further understand the role of this collagen receptor and other fibroblast integrins during health and in disease.

Cells are anchored in the extracellular matrix (ECM) via specific receptors belonging to different superfamilies, including the integrin family. Out of the 24 integrin heterodimers, α1β1, α2β1, α10β1 and α11β1 integrins act as primary receptors for native collagens ¹. ECM, integrins and the fibroblast are increasingly being recognized as being important in the control of the microenvironment ². The ECM, in addition to its supportive structural role, acts as a reservoir for growth factors, guides cell migration, influences cell signaling, cell growth, cell differentiation and direct angiogenesis. In normal epithelial tissue, the stromal compartment provides the important support for the normal function of the epithelium and other cells constituting an organ. The normal stroma is composed of orderly structured mesenchymal cells (including fibroblasts) and extracellular substances, vascular and lymphatic networks, and minimal immune cell infiltrate. Fibroblasts are cells of mesodermal or ectomesenchymal origin that reside in every tissue of the body. Sampling of fibroblasts from different location in the body has revealed that fibroblasts are characterized by a positional code ³. In addition, rather than being cells of a defined fixed phenotype, they appear to be heterogeneous, even within tissues like skin ⁴. Under certain conditions fibroblasts can be activated and differentiate into so-called myofibroblasts, which are contractile collagen-producing cells ⁵. This differentiation occurs during wound healing, fibrosis, and the desmoplastic reaction in the tumor stroma.

The traditional view of the fibroblast as that of a rather passive cell type that merely produces the constituents of the interstitial extracellular matrix, is now changing. This is in part the result from work in the field of tumor biology where a paradigm shift has occurred so that there is now a widespread understanding of the importance of the tumor microenvironment for tumorigenesis and tumor metastasis. One of the major cell types that seem to be important for conditioning the microenvironment is the fibroblast. The emerging view suggests that fibroblasts play a much more active part in maintaining tissue homeostasis and sustaining certain dynamic tissue events, than previously thought. In tumors, the stroma is an activated tissue, i.e. mechanisms are initiated that support dynamic and active tissue remodeling ². The activated status of many cells in the tumor stroma persists and has been likened to that of a non-healing wound ⁶. The changes that occur in the stroma during carcinogenesis include induction of fibroblasts proliferation, differentiation into myofibroblasts ⁵, altered amount and arrangement of stromal collagen, angiogenesis and increased immune and inflammatory cell infiltrates. Such changes are also reflected at biochemical and gene expression levels, as revealed by microarray studies comparing organ specific cancer versus normal tissues. Recent studies indicate that such changes in the stroma are not merely a bystander phenomenon, but play major roles in the process of carcinogenesis ⁷, including tumor cell growth, invasion, metastases, angiogenesis, and chemoresistance ^8-10. The detailed mechanisms of these processes, which are likely to be tumor and tissue specific, are however, still largely unknown.

In an effort to develop novel cancer therapeutics, there is currently intensive effort to better understand the dynamic interplay between the tumor stroma, ECM, fibroblasts, endothelial cells and immune response cells. Given the central role of the activated carcinoma-associated fibroblasts (CAFs) in tumor growth, it is of interest to target the tumor fibroblast in anti-fibrogenesis approaches. This is the focus of a FUGE II-supported project in our laboratory. In this work we are establishing spheroids as a model system to study tumor-stroma interactions.

In our work with collagen-binding integrins, we identified a novel integrin subunit, named integrin α11, which has been the focus of our work for more than 10 years ^11-14. Mice lacking this integrin are dwarfed, due to defective tooth structure, in turn reflecting a need for α11β1 on periodontal ligament fibroblasts during tooth eruption ¹⁵. In our continued work with this integrin it has become increasingly clear that α11β1 integrin might be a rather unique fibroblast marker From work with our existing mouse models, data is accumulating to suggest that α11β1 is functionally important in regulating tumor growth ¹⁶. From the tumor model, existing data suggest that a11 can work in a paracrine mode regulating IGF-II secretion ¹⁶. Some exciting years are thus ahead of us when the further detailed molecular mechanisms of α11β1 action need to be clarified. In these studies, subjecting our existing knockout mouse model to different challenging protocols as well as producing new animal models, which can validate and complement existing knockout mouse models, will be essential.

PROJECTS