Effect of distributional heterogeneity on the analysis of tumor hypoxia based on carbonic anhydrase IX

Iakovlev, Vladimir V.; Pintilie, Melania; Morrison, Andrew; Fyles, Anthony; Hill, Richard P.; Hedley, David W.

doi:10.1038/labinvest.3700680

Cited by 54 publications

(51 citation statements)

References 43 publications

(55 reference statements)

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“…The difference was smaller yet for adjusted values. This was in keeping with published innervations within scar tissue [21] [22] [26] [27].…”

Section: Resultssupporting

confidence: 76%

“…Ten images of random areas of the specimens were processed to generate two sets of binary (black & white bitmap) images: a set of images of all tissue including mesh filaments and a set of images excluding the mesh filaments. Selection, thresholding and image conversion were done using Photoshop SC6 (http://www.adobe.com/) and area measurements using image analysis software HAPI [21]- [23]. Median percentage of area occupied by the mesh material within the sampled tissue was 7.3% and an adjusted nerve density was corrected accordingly.…”

Section: Methodsmentioning

confidence: 99%

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Mesh-Related SIN Syndrome. A Surreptitious Irreversible Neuralgia and Its Morphologic Background in the Etiology of Post-Herniorrhaphy Pain

Bendavid¹,

Lou²,

Koch³

et al. 2014

IJCM

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Purpose: The ubiquitous use of synthetic materials in hernia surgery has brought about a new clinical syndrome: Surreptitious Irreversible Neuralgia (SIN). It is surreptitious because it is of slow onset, unsuspected and enigmatic to clinicians; irreversible because the pain is progressive, unrelenting and unresponsive to treatment. Removal of the mesh does not guarantee pain relief. Neuralgia following mesh insertion, when it occurs, remains a poorly understood phenomenon. Methods: Ten specimens in each group: virgin tissue, scar tissue and explanted mesh from the posterior inguinal wall were examined histologically to assess nerve density, nerve size and nerve and vessel ingrowth into the deformed mesh and within its pores. Results: There was no significant difference in nerve density between virgin, scar and mesh samples. All of the explanted meshes had nerves within the scar tissue encasing the mesh (interstitial infiltration). Nerve ingrowth through the pores of the mesh (micro-entrapment) was detected in 90% of the explanted mesh specimens. Additionally, nerves were detected entrapped within the folds and deformations of mesh explants. Ingrown vessels showed congestion and focal fibrin thrombi. Conclusion: The presence of mesh does not significantly affect nerve density, while the nerves and their terminal ends are in a vulnerable position about the mesh and within its pores. These pores need to be viewed as "mini-compartments" of biological tissue where the vasculature, nerves and their receptors are exposed to potential mechanical and chemical factors:

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“…The difference was smaller yet for adjusted values. This was in keeping with published innervations within scar tissue [21] [22] [26] [27].…”

Section: Resultssupporting

confidence: 76%

Section: Methodsmentioning

confidence: 99%

Mesh-Related SIN Syndrome. A Surreptitious Irreversible Neuralgia and Its Morphologic Background in the Etiology of Post-Herniorrhaphy Pain

Bendavid¹,

Lou²,

Koch³

et al. 2014

IJCM

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“…44,45 However, our own studies of CA-9 in primary cervix carcinomas have suggested that heterogeneity of expression in different regions of the tumors may confound the predictive value of CA-9 expression measured in biopsies from such tumors. 36,46 As noted above, analysis of cell suspensions derived from biopsies may help to reduce the effect of heterogeneity. We have not addressed heterogeneity directly in this study, but it is of interest that the CA-9 positivity observed for the immunohistochemical analysis (Figure 3b) correlates in magnitude with the mean percentage of CA-9-positive cells sorted from the hypoxic and normoxic populations in both primary cervix and lymph node metastatic tumors (Figure 1).…”

Section: Sorting Hypoxic Cells From Tumors N Chaudary and Rp Hillmentioning

confidence: 99%

“…32 CA-9 is a well-known marker of tumor hypoxia identifiable by its intense surface membrane staining, commonly seen in hypoxic tissue. [33][34][35] Recently, Iakovlev et al 36 showed that CA-9 labeling was correlated with direct pO 2 measurements in cervical carcinoma and that there was significant intratumoral heterogeneity. Our study further supports CA-9 as a suitable marker for identifying hypoxia and presents findings showing upregulated expression of a series of metastasis-related genes in sorted CA-9-positive (hypoxic) cells.…”

mentioning

confidence: 99%

Increased expression of metastasis-related genes in hypoxic cells sorted from cervical and lymph nodal xenograft tumors

Chaudary

Hill

2009

Laboratory Investigation

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Solid tumors contain regions of poor oxygenation that relate to the abnormal vascular network. Clinical investigations in cervical carcinoma have shown that positive lymph node status in patients with cervical carcinoma correlates with hypoxia. Earlier, in an orthotopic cervical cancer model, we had shown that exposure to acute hypoxia enhances lymph node metastasis. This study describes a technique for sorting hypoxic cells directly from the cervical xenograft model and reports the expression of 'metastasis-related' genes in hypoxic cells from xenografted cervix and lymph node tumors. Tumor cells were sorted on the basis of DsRed fluorescence and the sub-population of hypoxic cells was sorted on the basis of carbonic anhydrase-9 (CA-9) expression. Quantitative RT-PCR was conducted to measure changes in gene expression in the hypoxic cells sorted from primary cervix tumors and lymph node metastases. Immunohistochemistry was used to track changes in protein expression in sections of the same tumors. Metastasis-related genes, CXCR4, uPAR, VEGFC, Hdm2, and OPN, were observed to be upregulated at gene and protein levels in the primary tumors and nodal metastasis from the orthotopic transplants. In particular, the hypoxic cells sorted from orthotopically transplanted cervix tumors and their lymph node metastases from mice exposed to cyclic (intermittent) hypoxia showed higher levels of expression of these genes. These results are consistent with the hypothesis that these genes may be involved in regulating lymph node metastasis in cervical cancers under hypoxic conditions and provide support to the concept cyclic hypoxia that plays an important role in this process. Our methodological study emphasizes the technique of cell sorting to identify hypoxic cells using CA-9, which may aid in improving prognostic capabilities and in designing rational therapeutic strategies by focusing on hypoxia-specific gene expression profiles of patients. The technique can be applied to identify other potential 'hypoxia-related' genes of interest for tumor growth and metastasis.

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“…Although pancreatic cancers are often considered as being hypoxic, most publications have used histologic surrogate markers for hypoxia that might be compromised by surgical ischemic time or by sampling error due to the heterogeneous distribution of hypoxia in tumor tissue (23,24). Direct evidence that pancreatic cancers are hypoxic is limited to a small study in which intraoperative pO 2 measurements were made by inserting needle electrodes into the exposed tumor (25).…”

Section: Introductionmentioning

confidence: 99%

Hypoxia Predicts Aggressive Growth and Spontaneous Metastasis Formation from Orthotopically Grown Primary Xenografts of Human Pancreatic Cancer

et al. 2011

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Hypoxia in solid tumors is associated with treatment resistance and increased metastatic potential. Although hypoxia has been reported in pancreatic cancer patients, there is little direct evidence that this contributes to their overall poor prognosis. To address this, we examined the associations between hypoxia and biological aggression in a series of patient-derived xenografts grown orthotopically. Early passage xenografts were established from 16 patients undergoing surgery for pancreatic cancer and maintained in the pancreas of immune-deprived mice. Hypoxic cells were labeled using the 2-nitroimidazole probe EF5 and stained for immunofluorescence microscopy of tissue sections or as cell suspensions for flow cytometry. Bromodeoxyuridine (BrdUrd) uptake, microvessel density, cleaved caspase-3, and the differentiation markers E-cadherin, cytokeratin 19, and vimentin were analyzed in relation to hypoxia. Orthotopic implants closely resembled the histology of the original surgical samples. The 16 primary xenografts showed a wide range in their growth rates and metastatic potential, reminiscent of the spectrum of behavior seen in the clinic. EF5 labeling, tumor growth rates, and metastatic patterns were highly consistent within replicates, indicating a significant transmissible (genetic or epigenetic) component. Hypoxia was highly correlated with rapid tumor growth, increased BrdUrd uptake, and with spontaneous metastasis formation. mRNA expression analysis showed increased expression of genes involved in cell survival and proliferation in the hypoxic models. The results suggest that hypoxia is a major adverse prognostic factor in pancreatic cancer patients and support the introduction of techniques to measure hypoxia directly in patients and the development of treatment protocols to target hypoxia. Cancer Res; 71(8); 3110-20. Ó2011 AACR.

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Effect of distributional heterogeneity on the analysis of tumor hypoxia based on carbonic anhydrase IX

Cited by 54 publications

References 43 publications

Mesh-Related SIN Syndrome. A Surreptitious Irreversible Neuralgia and Its Morphologic Background in the Etiology of Post-Herniorrhaphy Pain

Mesh-Related SIN Syndrome. A Surreptitious Irreversible Neuralgia and Its Morphologic Background in the Etiology of Post-Herniorrhaphy Pain

Increased expression of metastasis-related genes in hypoxic cells sorted from cervical and lymph nodal xenograft tumors

Hypoxia Predicts Aggressive Growth and Spontaneous Metastasis Formation from Orthotopically Grown Primary Xenografts of Human Pancreatic Cancer

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