CD44 and RHAMM Are Microenvironmental Sensors with Dual Metastasis Promoter and Suppressor Functions.

The progression of primary tumors to metastases remains a significant roadblock to the treatment of most cancers. Emerging evidence has identified genes that specifically affect metastasis and are potential therapeutic targets for managing tumor progression. However, these genes can have dual tumor promoter and suppressor functions that are contextual in manifestation, and that complicate their development as targeted therapies. CD44 and RHAMM/HMMR are examples of multifunctional proteins that can either promote or suppress metastases, as demonstrated in experimental models. These two proteins can be viewed as microenvironmental sensors and this minireview addresses the known mechanistic underpinnings that may determine their metastasis suppressor versus promoter functions. Leveraging this mechanistic knowledge for CD44, RHAMM, and other multifunctional proteins is predicted to improve the precision of therapeutic targeting to achieve more effective management of metastasis.

Hyaluronan Functions in Wound Repair That Are Captured to Fuel Breast Cancer Progression.

Signaling from an actively remodeling extracellular matrix (ECM) has emerged as a critical factor in regulating both the repair of tissue injuries and the progression of diseases such as metastatic cancer. Hyaluronan (HA) is a major component of the ECM that normally functions in tissue injury to sequentially promote then suppress inflammation and fibrosis, a duality in which is featured, and regulated in, wound repair. These essential response-to-injury functions of HA in the microenvironment are hijacked by tumor cells for invasion and avoidance of immune detection. In this review, we first discuss the numerous size-dependent functions of HA and emphasize the multifunctional nature of two of its receptors (CD44 and RHAMM) in regulating the signaling duality of HA in excisional wound healing. This is followed by a discussion of how HA metabolism is de-regulated in malignant progression and how targeting HA might be used to better manage breast cancer progression.

Genetic deletion of receptor for hyaluronan-mediated motility (Rhamm) attenuates the formation of aggressive fibromatosis (desmoid tumor).

Aggressive fibromatosis (desmoid tumor) is a locally invasive soft tissue neoplasm associated with mutations resulting in beta-catenin-mediated transcriptional activation. This tumor is composed of cells with histological and molecular characteristics common to proliferating mesenchymal cells of dermal wounds. Using immunohistochemistry and RT-PCR, we show that Rhamm, a protein with an important role in wound healing and neoplastic progression, is also expressed at high levels in aggressive fibromatosis. A mouse harboring a targeted deletion in Rhamm was generated, resulting in viable Rhamm-/- animals. Rhamm-/- mice were crossed with Apc/Apc1638N mice, which harbor a targeted mutation in the Apc gene predisposing animals to gastrointestinal and aggressive fibromatosis tumors. Rhamm deficiency significantly decreased the number of aggressive fibromatosis tumors formed, but did not alter the number of gastrointestinal polyps. Cell culture studies show that Rhamm regulates cell proliferation in both fibroblasts and fibromatosis cells under conditions of low density, but not high density. These results suggest that Rhamm regulates proliferation of cells with sparse cell-cell contacts, such as occurs in aggressive fibromatosis; provides the first genetic evidence implicating Rhamm in tumor pathology; and suggest Rhamm blockade as a potential therapeutic target for this otherwise difficult-to-treat neoplasm.