Discoidin Domain Receptors: Potential Actors and Targets in Cancer

Abstract

The extracellular matrix critically controls cancer cell behavior by inducing several signaling pathways through cell membrane receptors. Besides conferring structural properties to tissues around the tumor, the extracellular matrix is able to regulate cell proliferation, survival, migration, and invasion. Among these receptors, the integrins family constitutes a major class of receptors that mediate cell interactions with extracellular matrix components. Twenty years ago, a new class of extracellular matrix receptors has been discovered. These tyrosine kinase receptors are the two discoidin domain receptors DDR1 and DDR2. DDR1 was first identified in the Dictyostelium discoideum and was shown to mediate cell aggregation. DDR2 shares highly conserved sequences with DDR1. Both receptors are activated upon binding to collagen, one of the most abundant proteins in extracellular matrix. While DDR2 can only be activated by fibrillar collagen, particularly types I and III, DDR1 is mostly activated by type I and IV collagens. In contrast with classical growth factor tyrosine kinase receptors which display a rapid and transient activation, DDR1 and DDR2 are unique in that they exhibit delayed and sustained receptor phosphorylation upon binding to collagen. Recent studies have reported differential expression and mutations of DDR1 and DDR2 in several cancer types and indicate clearly that these receptors have to be taken into account as new players in the different aspects of tumor progression, from non-malignant to highly malignant and invasive stages. This review will discuss the current knowledge on the role of DDR1 and DDR2 in malignant transformation, cell proliferation, epithelial to mesenchymal transition, migratory, and invasive processes, and finally the modulation of the response to chemotherapy. These new insights suggest that DDR1 and DDR2 are new potential targets in cancer therapy.

From transformation to metastasis: deconstructing the extracellular matrix in breast cancer

“…It is shown that the discoidin receptor, DDR1, facilitates chemoresistance via the NF-κβ pathway [98]. Given that discoidin receptors promote tumor progression independently, as well as through interactions with integrins, such as α 2 β 1 integrin [99], it will be worthwhile to investigate their role, together with that of integrins, in promoting chemoresistance.…”

Suppressing miR-199a-3p by promoter methylation contributes to tumor aggressiveness and cisplatin resistance of ovarian cancer through promoting DDR1 expression

“…DDRs regulate important aspects of cellular processes including proliferation, migration, adhesion, and ECM remodeling by interacting with several types of collagen [6]. In several human cancers, such as breast cancer, lung cancer, and hepatocarcinoma, dysregulated DDRs have been observed to be related with tumor development [7].…”

Tumor-extrinsic discoidin domain receptor 1 promotes mammary tumor growth by regulating adipose stromal interleukin 6 production in mice

“…To date, published studies of DDR1 in cancer have been limited to its action in tumor cells 20,21 . Using genetically engineered mice and syngeneic tumor models, we demonstrate the importance of host DDR1 in tumor growth, thus significantly extending the current understanding of DDR1 tumor-promoting function.…”

“…DDR1 is predominantly expressed in normal epithelial cells and its aberrant expression is associated with multiple solid cancer types. For these reasons, the current literature on DDR1 function in cancer biology has exclusively been focused on its activity in tumor cells [20][21][22] . However, comparative gene expression profiling shows that stromal DDR1 expression in invasive breast cancer is significantly elevated versus normal breast stroma 23 (6.4-fold, p= 1x10 -15 ), suggesting a possible DDR1 function in stromal cells during cancer progression.…”