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Oskarsson T.,Heidelberg Institute for Stem Cell Technology and Experimental Medicine | Oskarsson T.,German Cancer Research Center
Breast | Year: 2013

The extracellular matrix (ECM) is composed of highly variable and dynamic components that regulate cell behavior. The protein composition and physical properties of the ECM govern cell fate through biochemical and biomechanical mechanisms. This requires a carefully orchestrated and thorough regulation considering that a disturbed ECM can have serious consequences and lead to pathological conditions like cancer. In breast cancer, many ECM proteins are significantly deregulated and specific matrix components promote tumor progression and metastatic spread. Intriguingly, several ECM proteins that are associated with breast cancer development, overlap substantially with a group of ECM proteins induced during the state of tissue remodeling such as mammary gland involution. Fibrillar collagens, fibronectin, hyaluronan and matricellular proteins are matrix components that are common to both involution and cancer. Moreover, some of these proteins have in recent years been identified as important constituents of metastatic niches in breast cancer. In addition, specific ECM molecules, their receptors or enzymatic modifiers are significantly involved in resistance to therapeutic intervention. Further analysis of these ECM proteins and the downstream ECM mediated signaling pathways may provide a range of possibilities to identify druggable targets against advanced breast cancer. © 2013 Elsevier Ltd.

Acharyya S.,Sloan Kettering Cancer Center | Oskarsson T.,Sloan Kettering Cancer Center | Oskarsson T.,Heidelberg Institute for Stem Cell Technology and Experimental Medicine | Vanharanta S.,Sloan Kettering Cancer Center | And 11 more authors.
Cell | Year: 2012

Metastasis and chemoresistance in cancer are linked phenomena, but the molecular basis for this link is unknown. We uncovered a network of paracrine signals between carcinoma, myeloid, and endothelial cells that drives both processes in breast cancer. Cancer cells that overexpress CXCL1 and 2 by transcriptional hyperactivation or 4q21 amplification are primed for survival in metastatic sites. CXCL1/2 attract CD11b+Gr1+ myeloid cells into the tumor, which produce chemokines including S100A8/9 that enhance cancer cell survival. Although chemotherapeutic agents kill cancer cells, these treatments trigger a parallel stromal reaction leading to TNF-α production by endothelial and other stromal cells. TNF-α via NF-kB heightens the CXCL1/2 expression in cancer cells, thus amplifying the CXCL1/2-S100A8/9 loop and causing chemoresistance. CXCR2 blockers break this cycle, augmenting the efficacy of chemotherapy against breast tumors and particularly against metastasis. This network of endothelial-carcinoma-myeloid signaling interactions provides a mechanism linking chemoresistance and metastasis, with opportunities for intervention. © 2012 Elsevier Inc.

Ehninger A.,German Cancer Research Center | Trumpp A.,German Cancer Research Center | Trumpp A.,Heidelberg Institute for Stem Cell Technology and Experimental Medicine
Journal of Experimental Medicine | Year: 2011

Stem cell niches are defined as the cellular and molecular microenvironments that regulate stem cell function together with stem cell autonomous mechanisms. This includes control of the balance between quiescence, self-renewal, and differentiation, as well as the engagement of specific programs in response to stress. In mammals, the best understood niche is that harboring bone marrow hematopoietic stem cells (HSCs). Recent studies have expanded the number of cell types contributing to the HSC niche. Perivascular mesenchymal stem cells and macrophages now join the previously identified sinusoidal endothelial cells, sympathetic nerve fibers, and cells of the osteoblastic lineage to form similar, but distinct, niches that harbor dormant and self-renewing HSCs during homeostasis and mediate stem cell mobilization in response to granulocyte colony-stimulating factor. © 2011 Ehninger and Trumpp.

Oskarsson T.,Heidelberg Institute for Stem Cell Technology and Experimental Medicine | Massague J.,Sloan Kettering Cancer Center
EMBO Journal | Year: 2012

Metastatic niches support the survival and fitness of disseminated tumour cells (DTCs) in otherwise inhospitable tissue environments. The components of metastatic niches have remained a matter of conjecture, but recent reports, including one in a current issue of Nature, point at the extracellular matrix (ECM) proteins periostin and tenascin C (TNC) as key metastatic niche molecules. By enhancing Wnt and Notch signalling in cancer cells, these proteins provide physical as well as signalling support for metastasis-initiating cells. These findings underscore the importance of the ECM environment in cancer and provide potential drug targets against metastasis. © 2012 European Molecular Biology Organization | All Rights Reserved.

Heidelberg Institute for Stem Cell Technology and Experimental Medicine | Date: 2012-03-08

This invention relates to a novel method for analyzing circulating tumor cells of a patient for the presence of metastasis-initiating cells. The method comprises the step of detecting cells exhibiting the simultaneous presence of c-MET, CD44 and CD47. The invention further relates to novel kits, novel methods for treating patients, and novel bifunctional analytes.

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