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:

  1. 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.
  2. 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.
  3. 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.
  4. There was no observed relationship between VEGF expression and the microvascular density in the patient samples.
  5. 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.


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