The Bone Niche of Chondrosarcoma: A Sanctuary for Drug Resistance, Tumour Growth and also a Source of New Therapeutic Targets

David, Emmanuelle; Blanchard, Frédéric; Heymann, Marie-Françoise; Pinieux, Gonzague de; Gouin, F.; Rédini, Françoise; Heymann, Dominique

doi:10.1155/2011/932451

Cited by 61 publications

(54 citation statements)

References 76 publications

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“…Even with surgical treatment, local recurrence, metastasis and death do occur in a subset of patients with chondrosarcoma . For this reason, significant research effort has been dedicated to understand the biological basis for chondrosarcoma pathogenesis and identify pharmacologic targets to aid in adjuvant treatment . Despite increasing understanding of chondrosarcoma biology, there are no available chemotherapeutic strategies to improve surgical outcomes.…”

Section: Discussionmentioning

confidence: 99%

Osteoclast inhibition impairs chondrosarcoma growth and bone destruction

et al. 2014

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Because Chondrosarcoma is resistant to available chemotherapy and radiation regimens, wide resection is the mainstay in treatment, which frequently results in high morbidity and which may not prevent local recurrence. There is a clear need for improved adjuvant treatment of this malignancy. We have observed the presence of osteoclasts in the microenvironment of chondrosarcoma in human pathological specimens. We utilized the Swarm rat chondrosarcoma (SRC) model to test the hypothesis that osteoclasts affect chondrosarcoma pathogenesis. We implanted SRC tumors in tibia of Sprague-Dawley rats and analyzed bone histologically and radiographically for bone destruction and tumor growth. At three weeks, tumors invaded local bone causing cortical disruption and trabecular resorption. Bone destruction was accompanied by increased osteoclast number and resorbed bone surface. Treatment of rats with the zoledronic acid prevented cortical destruction, inhibited trabecular resorption, and resulted in decreased tumor volume in bone. To confirm that inhibition of osteoclasts per se, and not off-target effects of drug, was responsible for the prevention of tumor growth and bone destruction, we implanted SRC into osteopetrotic rat tibia. SRC-induced bone destruction and tumor growth were impaired in osteopetrotic bone compared with control bone. The results from our animal model demonstrate that osteoclasts contribute to chondrosarcoma-mediated bone destruction and tumor growth and may represent a therapeutic target in particular chondrosarcoma patients. ß

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Section: Discussionmentioning

confidence: 99%

Osteoclast inhibition impairs chondrosarcoma growth and bone destruction

et al. 2014

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“…While the concept of a tissue sanctuary has previously been reported in cancer biology, it was mostly used in reference to metastatic brain sanctuaries that arise due to the blood brain barrier [48,56] and bone marrow sanctuaries that arise due to their protective structure [12,41]. Recently, this concept of drug sanctuaries has been adopted in the context of acquired drug resistance [15].…”

Section: Tissue Niches and Sanctuaries And Their Relation To Resismentioning

confidence: 99%

Microenvironmental Niches and Sanctuaries: A Route to Acquired Resistance

Pérez-Velázquez

Gevertz

Karolak

et al. 2016

Advances in Experimental Medicine and Biology

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A tumor vasculature that is functionally abnormal results in irregular gradients of metabolites and drugs within the tumor tissue. Recently, significant efforts have been committed to experimentally examine how cellular response to anti-cancer treatments varies based on the environment in which the cells are grown. In vitro studies point to specific conditions in which tumor cells can remain dormant and survive the treatment. In vivo results suggest that cells can escape the effects of drug therapy in tissue regions that are poorly penetrated by the drugs. Better understanding how the tumor microenvironments influence the emergence of drug resistance in both primary and metastatic tumors may improve drug development and the design of more effective therapeutic protocols. This chapter presents a hybrid agent-based model of the growth of tumor micrometastases and explores how microenvironmental factors can contribute to the development of acquired resistance in response to a DNA damaging drug. The specific microenvironments of interest in this work are tumor hypoxic niches and tumor normoxic sanctuaries with poor drug penetration. We aim to quantify how spatial constraints of limited drug transport and quiescent cell survival contribute to the development of drug resistant tumors.

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“…ITGA6 has been identified as a stem cell marker and is expressed by over 70% of advanced prostate carcinomas. Targeting laminin-binding integrins is particularly relevant to bone metastatic lesions as bone is a laminin-rich environment that provides a protective adhesion site for early metastatic tumors to survive standard chemotherapeutic agents (38–40). Importantly, the J8H antibody will block tumor migration without altering cell adhesion to laminin, as loss of ITGA6 adhesion by either circulating auto-antibody or ITGA6 mutation has been associated with epithelial blistering and basement membrane separation (41, 42).…”

Section: Discussionmentioning

confidence: 99%

Targeting Integrin α6 Stimulates Curative-Type Bone Metastasis Lesions in a Xenograft Model

Landowski

Gard

Pond

et al. 2014

Molecular Cancer Therapeutics

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Laminin binding integrin receptors are key mediators of epithelial cell migration and tumor metastasis. Recent studies have demonstrated a role for the alpha 6 integrin (ITGA6/CD49f) in maintaining stem cell compartments within normal bone marrow and in residency of tumors metastatic to bone. In this study, we tested a function-blocking antibody specific for ITGA6, called J8H, to determine if pre-existing cancer lesions in bone could be slowed and/or animal survival improved. Human prostate tumors were established by intracardiac injection into male severe combined immunodeficient (SCID) mice and treatment with J8H antibody was initiated after one week. Tumor progression was monitored by micro computed tomography (CT) imaging of skeletal lesions. Animals that received weekly injections of the anti-ITGA6 antibody showed radiographic progression in only 40% of osseous tumors (femur or tibia), compared to control animals, where 80% of the lesions (femur or tibia) showed progression at 5 weeks. Kaplan-Meier survival analysis demonstrated a significant survival advantage for J8H-treated animals. Unexpectedly, CT image analysis revealed an increased proportion of bone lesions displaying a sclerotic rim of new bone formation, encapsulating the arrested lytic lesions in animals that received the anti-ITGA6 antibody treatment. Histopathology of the sclerotic lesions demonstrated well-circumscribed tumor within bone, surrounded by fibrosis. These data suggest that systemic targeting of the ITGA6-dependent function of established tumors in bone may offer a non-cytotoxic approach to arrest the osteolytic progression of metastatic prostate cancer, thereby providing a new therapeutic strategy for advanced disease.

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The Bone Niche of Chondrosarcoma: A Sanctuary for Drug Resistance, Tumour Growth and also a Source of New Therapeutic Targets

Cited by 61 publications

References 76 publications

Osteoclast inhibition impairs chondrosarcoma growth and bone destruction

Osteoclast inhibition impairs chondrosarcoma growth and bone destruction

Microenvironmental Niches and Sanctuaries: A Route to Acquired Resistance

Targeting Integrin α6 Stimulates Curative-Type Bone Metastasis Lesions in a Xenograft Model

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