Moreover, hypoxic conditions, a hallmark of the TME, are closely related to initiation of tumor angiogenesis, whereby the ubiquitin-proteasome pathway of hypoxia inducible factor-1 (HIF-1) is inhibited under hypoxic conditions, which leads to intracellular HIF-1 complex accumulation that promotes initiation of transcription of pro-angiogenic genes. Here, HIF1A is linked to neoplasm.