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Despite the hypervascularization seen in solid tumors, hypoxic conditions can result. This is thought to be caused by an imbalance between the rate of tumor cell proliferation and new endothelial cell formation, as well as disorganization of the new vascular supply (2,3). A state of extracellular hypertension is produced, leading to decrease blood flow. While most normal tissues cannot endure nutrient deficient states, it is known that most solid tumors can persist and sometimes proliferate under hypoxic conditions. This is not only a competitive advantage for the tumor (versus normal) cells, the extracellular hypertension, by impeding blood flow, leads to poor delivery of chemotherapy(4).
It has been shown that tumor cells can exhibit proliferative change under hypoxix conditions in a cell line specific manner. This is true also of Osteosarcoma. The main markers used to assess growth in osteosarcoma samples have been Hypoxia-inducible transcription factor 1a (HIF-1a) and vascular endothelial growth factor (VEGF).
Hypoxia-inducible transcription factor (HIF-1) is an important element in the cellular response to hypoxia. HIF-1a subunit is overexpressed in colon, breast, gastric, lung, skin, ovarian, pancreatic, prostate, and renal carcinomas and associated with cell proliferation (5). This marker has also been shown to activate vascular endothelial growth factor (VEGF).
In a recent study (1) by Mizobuchi and Healey from Memorial Sloan Kettering, the following findings were published:
- In 61% of HIF-1a-positive patients, metastases were present, representing a 4.3-fold greater risk for having metastatic disease in patients with HIF-1a expression compared to that of HIF-1a-negative patients.
- VEGF protein expression was seen in 73% of patients. More specifically, by an unclear mechanism, an association between VEGF expression and female gender was demonstrated.
- An insignificant trend for higher frequency of VEGF expression was shown to be present in the high-grade as compared to low-grade osteosarcoma. However, a larger cohort of low grade osteosarcoma is required.
- There was no observed relationship between VEGF expression and the microvascular density in the patient samples.
- There was no observed association between the Ki-67 labeling index and clinical data. The high proliferative potential of tumor cells as a prognostic factor has given variable results.
In general, tumor hypoxia and proliferation may be indicative of clinical outcome (prognosis defined by chemotherapy response and metastatic phenotype) and as such, these markers might serve as proxies for prognosis.
References:
1.
Mizobuchi H, García-Castellano JM, Philip S, Healey JH, Gorlick R, 2008. "Hypoxia markers in human osteosarcoma: an exploratory study." Clin Orthop Relat Res 466 (9): 2052-9 [PubMed]
Abstract:
Neoplastic cells growing under hypoxic conditions exhibit a more aggressive phenotype by activating a cascade of molecular events partly mediated by hypoxia-inducible transcription factor (HIF-1alpha) and vascular endothelial growth factor (VEGF). The roles of these markers have been studied previously in several cancer lines. We ascertained the frequency of HIF-1alpha expression, VEGF expression, the degree of neovascularization, and cell proliferation in osteosarcoma samples. Samples from osteosarcoma patients were assessed for HIF-1alpha and VEGF protein expression using immunohistochemistry, neovascularization using antibodies for Factor VIII, and cell proliferation using the Ki-67 labeling index. Associations between these parameters and clinical features were examined. HIF-1alpha staining was positive in 35% of patients and metastases were present in 61% of these HIF-1alpha-positive patients. VEGF protein expression was detected in 69% of patients, 92% of whom were female. We observed an insignificant trend for a higher frequency of VEGF expression in the high-grade as compared to low-grade osteosarcoma. We observed no association between vascular density and proliferation index and any clinical parameters. We found an association between HIF-1alpha expression and metastatic disease and between VEGF expression and female gender.
2.
Pan KM, Baldwin M, Nguyen J, Gasset M, Serban A, Groth D, Mehlhorn I, Huang Z, Fletterick RJ, Cohen FE, 1993. "Conversion of alpha-helices into beta-sheets features in the formation of the scrapie prion proteins." Proc Natl Acad Sci U S A 90 (23): 10962-6 [PubMed]
Abstract:
Prions are composed largely, if not entirely, of prion protein (PrPSc in the case of scrapie). Although the formation of PrPSc from the cellular prion protein (PrPC) is a post-translational process, no candidate chemical modification was identified, suggesting that a conformational change features in PrPSc synthesis. To assess this possibility, we purified both PrPC and PrPSc by using nondenaturing procedures and determined the secondary structure of each. Fourier-transform infrared (FTIR) spectroscopy demonstrated that PrPC has a high alpha-helix content (42%) and no beta-sheet (3%), findings that were confirmed by circular dichroism measurements. In contrast, the beta-sheet content of PrPSc was 43% and the alpha-helix 30% as measured by FTIR. As determined in earlier studies, N-terminally truncated PrPSc derived by limited proteolysis, designated PrP 27-30, has an even higher beta-sheet content (54%) and a lower alpha-helix content (21%). Neither PrPC nor PrPSc formed aggregates detectable by electron microscopy, while PrP 27-30 polymerized into rod-shaped amyloids. While the foregoing findings argue that the conversion of alpha-helices into beta-sheets underlies the formation of PrPSc, we cannot eliminate the possibility that an undetected chemical modification of a small fraction of PrPSc initiates this process. Since PrPSc seems to be the only component of the "infectious" prion particle, it is likely that this conformational transition is a fundamental event in the propagation of prions.
3.
Vaupel P, Mayer A, 2007. "Hypoxia in cancer: significance and impact on clinical outcome." Cancer Metastasis Rev 26 (2): 225-39 [PubMed]
Abstract:
Hypoxia, a characteristic feature of locally advanced solid tumors, has emerged as a pivotal factor of the tumor (patho-)physiome since it can promote tumor progression and resistance to therapy. Hypoxia represents a "Janus face" in tumor biology because (a) it is associated with restrained proliferation, differentiation, necrosis or apoptosis, and (b) it can also lead to the development of an aggressive phenotype. Independent of standard prognostic factors, such as tumor stage and nodal status, hypoxia has been suggested as an adverse prognostic factor for patient outcome. Studies of tumor hypoxia involving the direct assessment of the oxygenation status have suggested worse disease-free survival for patients with hypoxic cervical cancers or soft tissue sarcomas. In head & neck cancers the studies suggest that hypoxia is prognostic for survival and local control. Technical limitations of the direct O(2) sensing technique have prompted the use of surrogate markers for tumor hypoxia, such as hypoxia-related endogenous proteins (e.g., HIF-1alpha, GLUT-1, CA IX) or exogenous bioreductive drugs. In many - albeit not in all - studies endogenous markers showed prognostic significance for patient outcome. The prognostic relevance of exogenous markers, however, appears to be limited. Noninvasive assessment of hypoxia using imaging techniques can be achieved with PET or SPECT detection of radiolabeled tracers or with MRI techniques (e.g., BOLD). Clinical experience with these methods regarding patient prognosis is so far only limited. In the clinical studies performed up until now, the lack of standardized treatment protocols, inconsistencies of the endpoints characterizing the oxygenation status and methodological differences (e.g., different immunohistochemical staining procedures) may compromise the power of the prognostic parameter used.
4.
Jain RK, 2005. "Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy." Science 307 (5706): 58-62 [PubMed]
Abstract:
Solid tumors require blood vessels for growth, and many new cancer therapies are directed against the tumor vasculature. The widely held view is that these antiangiogenic therapies should destroy the tumor vasculature, thereby depriving the tumor of oxygen and nutrients. Here, I review emerging evidence supporting an alternative hypothesis-that certain antiangiogenic agents can also transiently "normalize" the abnormal structure and function of tumor vasculature to make it more efficient for oxygen and drug delivery. Drugs that induce vascular normalization can alleviate hypoxia and increase the efficacy of conventional therapies if both are carefully scheduled. A better understanding of the molecular and cellular underpinnings of vascular normalization may ultimately lead to more effective therapies not only for cancer but also for diseases with abnormal vasculature, as well as regenerative medicine, in which the goal is to create and maintain a functionally normal vasculature.
5.
Zhong H, De Marzo AM, Laughner E, Lim M, Hilton DA, Zagzag D, Buechler P, Isaacs WB, Semenza GL, Simons JW, 1999. "Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases." Cancer Res 59 (22): 5830-5 [PubMed]
Abstract:
Neovascularization and increased glycolysis, two universal characteristics of solid tumors, represent adaptations to a hypoxic microenvironment that are correlated with tumor invasion, metastasis, and lethality. Hypoxia-inducible factor 1 (HIF-1) activates transcription of genes encoding glucose transporters, glycolytic enzymes, and vascular endothelial growth factor. HIF-1 transcriptional activity is determined by regulated expression of the HIF-1alpha subunit. In this study, HIF-1alpha expression was analyzed by immunohistochemistry in 179 tumor specimens. HIF-1alpha was overexpressed in 13 of 19 tumor types compared with the respective normal tissues, including colon, breast, gastric, lung, skin, ovarian, pancreatic, prostate, and renal carcinomas. HIF-1alpha expression was correlated with aberrant p53 accumulation and cell proliferation. Preneoplastic lesions in breast, colon, and prostate overexpressed HIF-1alpha, whereas benign tumors in breast and uterus did not. HIF-1alpha overexpression was detected in only 29% of primary breast cancers but in 69% of breast cancer metastases. In brain tumors, HIF-1alpha immunohistochemistry demarcated areas of angiogenesis. These results provide the first clinical data indicating that HIF-1alpha may play an important role in human cancer progression.
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Sat Oct 11 08:23:37 PDT 2008
Sat Oct 11 08:23:38 PDT 2008
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