Microenvironmental Effects on Tumour Progression and Metastasis

Måseide, Kårstein; Kalliomäki, Tuula; Hill, Rićhard P.

doi:10.1007/1-4020-3414-8_1

Cited by 5 publications

(6 citation statements)

References 109 publications

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“…A large percentage of aggressive clinical tumors display regions with elevated levels of lactic acid, and areas of lactic acid production can be diffusely spread across large regions of the tumor. The elevation in lactic acid level correlates with the lower pH of tumors . There is, however, considerable variability between tumor types; sarcoma and adenocarcinoma have pH values as low as 5.6, squamous cell carcinoma have pHs as low as 6.3, and melanoma have been measured as low as pH 6.8 …”

Section: Introductionmentioning

confidence: 99%

“…The elevation in lactic acid level correlates with the lower pH of tumors . There is, however, considerable variability between tumor types; sarcoma and adenocarcinoma have pH values as low as 5.6, squamous cell carcinoma have pHs as low as 6.3, and melanoma have been measured as low as pH 6.8 …”

Section: Introductionmentioning

confidence: 99%

“…The elevation in lactic acid level correlates with the lower pH of tumors. 35 cell carcinoma have pHs as low as 6.3, and melanoma have been measured as low as pH 6.8. 35 Because ELPs undergo a sharp phase change that can be isothermally triggered by a small change in pH, and because this pH responsiveness is controlled by the type and number of ionizable residues and MW of the ELP, in principle, it should be possible to synthesize ELPs that are designed to undergo their phase transition within a narrow, physiologically relevant range of pH that is optimized for delivery to a specific tumor type.…”

Section: Introductionmentioning

confidence: 99%

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Quantitative Model of the Phase Behavior of Recombinant pH-Responsive Elastin-Like Polypeptides

et al. 2010

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Quantitative models are required to engineer biomaterials with environmentally responsive properties. With this goal in mind, we developed a model that describes the pH dependent phase behavior of a class of stimulus responsive elastin-like polypeptides (ELPs) that undergo reversible phase separation in response to their solution environment. Under isothermal conditions, charged ELPs can undergo phase separation when their charge is neutralized. Optimization of this behavior has been challenging because the pH at which they phase separate, pHt, depends on their composition, molecular weight, concentration, and temperature. To address this problem, we developed a quantitative model to describe the phase behavior of charged ELPs that uses the Henderson-Hasselbalch relationship to describe the effect of side-chain ionization on the phase transition temperature of an ELP. The model was validated with pH-responsive ELPs that contained either acidic (Glu) or basic (His) residues. The phase separation of both ELPs fit this model across a range of pH. These results have important implications for applications of pH-responsive elastin-like polypeptides, because they provide a quantitative model for the rational design of pH responsive polypeptides whose transition can be triggered at a specified pH.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Quantitative Model of the Phase Behavior of Recombinant pH-Responsive Elastin-Like Polypeptides

et al. 2010

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“…Furthermore, during hypoxia, an intricate balance exists between factors that induce or counteract apoptosis, or even stimulate proliferation. 4,[6][7][8][9][10][11][12][13] A hypoxic microenvironment in solid tumors seems to contribute to metastatic progression. [14][15][16][17][18] Cervical carcinoma spreading to the pelvic and aortic lymph nodes is a common occurrence, and is one of the primary determinants of outcome for patients.…”

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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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“…pH-Sensitive drug-delivery systems have received increasing interest in recent years as pH plays an important role in many biological process and some diseases such as asthma, peptic ulcer, heart disorders, hypertension and cancer [93]. For example, the pH found in healthy tissue or in the blood is different to that found in tumours due to tumour hypoxia and the production of substances such as lactic acid resulting from anaerobic metabolism and ion channel changes [94,95].…”

Section: Drug-delivery Systems Based On Ph-sensitive Elrsmentioning

confidence: 99%