The role of stromal cells and the tumour microenvironment in general in modulating tumour sensitivity is increasingly becoming a key consideration for the development of active anticancer therapeutics. Here, we discuss how these tumour-stromal interactions affect tumour cell signalling, survival, proliferation and drug sensitivity. Particular emphasis is placed on the ability of stromal cells to confer - to tumour cells - resistance or sensitization to different classes of therapeutics, depending on the specific microenvironmental context. The mechanistic understanding of these microenvironmental interactions can influence the evaluation and selection of candidate agents for various cancers, in both the primary site as well as the metastatic setting. Progress in in vitro screening platforms as well as orthotopic and 'orthometastatic' xenograft mouse models has enabled comprehensive characterization of the impact of the tumour microenvironment on therapeutic efficacy. These recent advances can hopefully bridge the gap between preclinical studies and clinical trials of anticancer agents.

The role of tumour-stromal interactions in modifying drug response: challenges and opportunities.

Primary vitreoretinal lymphoma (PVRL), also known as primary intraocular lymphoma, is a rare malignancy typically classified as a diffuse large B-cell lymphoma and most frequently develops in elderly populations. PVRL commonly masquerades as posterior uveitis and has a unique tropism for the retina and central nervous system (CNS). Over 15% of primary CNS lymphoma patients develop intraocular lymphoma, usually occurring in the retina and/or vitreous. Conversely, 65%-90% of PVRL patients develop CNS lymphoma. Consequently, PVRL is often fatal because of ultimate CNS association. Current PVRL animal models are limited and require further development. Typical clinical findings include vitreous cellular infiltration (lymphoma and inflammatory cells) and subretinal tumor infiltration as determined using dilated fundoscopy, fluorescent angiography, and optical coherent tomography. Currently, PVRL is most often diagnosed using both histology to identify lymphoma cells in the vitreous or retina and immunohistochemistry to indicate monoclonality. Additional adjuncts in diagnosing PVRL exist, including elevation of interleukin-10 levels in ocular fluids and detection of Ig(H) or T-cell receptor gene rearrangements in malignant cells. The optimal therapy for PVRL is not defined and requires the combined effort of oncologists and ophthalmologists. PVRL is sensitive to radiation therapy and exhibits high responsiveness to intravitreal methotrexate or rituximab. Although systemic chemotherapy alone can result in high response rates in patients with PVRL, there is a high relapse rate. Because of the disease rarity, international, multicenter, collaborative efforts are required to better understand the biology and pathogenesis of PVRL as well as to define both diagnostic markers and optimal therapies.

Primary Vitreoretinal Lymphoma: A Report from an International Primary Central Nervous System Lymphoma Collaborative Group Symposium

Outcomes for individuals with central nervous system (CNS) malignancies remain abysmal. A major challenge in managing these patients is the lack of reliable biomarkers to monitor tumor dynamics. Consequently, many patients undergo invasive surgical procedures to determine disease status or experience treatment delays when radiographic testing fails to show disease progression. We show here that primary CNS malignancies shed detectable levels of tumor DNA into the surrounding cerebrospinal fluid (CSF), which could serve as a sensitive and exquisitely specific marker for quantifying tumor burden without invasive biopsies. Therefore, assessment of such tumor-derived DNA in the CSF has the potential to improve the management of patients with primary CNS tumors.

/pdf/detection-of-tumor-derived-dna-in-cerebrospinal-fluid-of-1q0rqg8457.pdf

Detection of tumor-derived DNA in cerebrospinal fluid of patients with primary tumors of the brain and spinal cord

Identification of microRNAs in the cerebrospinal fluid as marker for primary diffuse large B-cell lymphoma of the central nervous system

BACKGROUND AND PURPOSE: There is evidence that increased tumor cellular density within diagnostic specimens of primary central nervous system lymphoma (PCNSL) may have significant prognostic implications. Because cellular density may influence measurements of apparent diffusion coefficient (ADC) by using diffusion-weighted MR imaging (DWI), we hypothesized that ADC measured from contrast-enhancing regions might correlate with clinical outcome in patients with PCNSL.

MATERIALS AND METHODS: PCNSL tumors from 18 immunocompetent patients, treated uniformly with methotrexate-based chemotherapy, were studied with pretherapeutic DWI. Enhancing lesions were diagnosed by pathologic analysis as high-grade B-cell lymphomas. Regions of interest were placed around all enhancing lesions allowing calculation of mean, 25th percentile (ADC25%), and minimum ADC values. Histopathologic tumor cellularity was quantitatively measured in all patients. High and low ADC groups were stratified by the median ADC value of the cohort. The Welch t test assessed differences between groups. The Pearson correlation examined relationships between ADC measurements and tumor cellular density. Single and multivariable survival analysis was performed.

RESULTS: We detected significant intra- and intertumor heterogeneity in ADC measurements. An inverse correlation between cellular density and ADC measurements was observed ( P < .05). ADC25% measurements less than the median value of 692 (low ADC group) were associated with significantly shorter progression-free and overall survival. Patients with improved clinical outcome were noted to exhibit a significant decrease in ADC measurements following high-dose methotrexate chemotherapy.

CONCLUSIONS: Our study provides evidence that ADC measurements within contrast-enhancing regions of PCNSL tumors may provide noninvasive insight into clinical outcome.

http://www.ajnr.org/content/ajnr/31/1/60.full.pdf

Diffusion-weighted MR imaging derived apparent diffusion coefficient is predictive of clinical outcome in primary central nervous system lymphoma.

Purpose Elucidation of the CSF proteome may yield insights into the pathogenesis of CNS disease. We tested the hypothesis that individual CSF proteins distinguish CNS lymphoma from benign focal brain lesions. Methods We used a liquid chromatography/mass spectrometry–based method to differentially quantify and identify several hundred CSF proteins in CNS lymphoma and control patients. We used enzyme-linked immunosorbent assay (ELISA) to confirm one of these markers in an additional validation set of 101 cases. Results Approximately 80 CSF proteins were identified and found to be present at significantly different concentrations, both higher and lower, in training and test studies, which were highly concordant. To further validate these observations, we defined in detail the expression of one of these candidate biomarkers, antithrombin III (ATIII). ATIII RNA transcripts were identified within CNS lymphomas, and ATIII protein was localized selectively to tumor neovasculature. Determination of ATIII concentra...

/pdf/protein-biomarker-identification-in-the-csf-of-patients-with-u26z5xw22u.pdf

Protein biomarker identification in the CSF of patients with CNS lymphoma.

Purpose: The prospect for advances in the treatment of patients with primary central nervous system lymphoma (PCNSL) is likely dependent on the systematic evaluation of its pathobiology. Animal models of PCNSL are needed to facilitate the analysis of its molecular pathogenesis and for the efficient evaluation of novel therapeutics. Experimental Design: We characterized the molecular pathology of CNS lymphoma tumors generated by the intracerebral implantation of Raji B lymphoma cells in athymic mice. Lymphoma cells were modified for bioluminescence imaging to facilitate monitoring of tumor growth and response to therapy. In parallel, we identified molecular features of lymphoma xenograft histopathology that are evident in human PCNSL specimens. Results: Intracerebral Raji tumors were determined to faithfully reflect the molecular pathogenesis of PCNSL, including the predominant immunophenotypic state of differentiation of lymphoma cells and their reactive microenvironment. We show the expression of interleukin-4 by Raji and other B lymphoma cell lines in vitro and by Raji tumors in vivo and provide evidence for a role of this cytokine in the M2 polarization of lymphoma macrophages both in the murine model and in diagnostic specimens of human PCNSL. Conclusion: Intracerebral implantation of Raji cells results in a reproducible and invasive xenograft model, which recapitulates the histopathology and molecular features of PCNSL, and is suitable for preclinical testing of novel agents. We also show for the first time the feasibility and accuracy of tumor bioluminescence in the monitoring of a highly infiltrative brain tumor.

/pdf/pathologic-correlates-of-primary-central-nervous-system-35376rbhb6.pdf

Juliana Karrim

Papers

Protein biomarker identification in the CSF of patients with CNS lymphoma.

Pathologic Correlates of Primary Central Nervous System Lymphoma Defined in an Orthotopic Xenograft Model