Researchers from Rice University have developed a new model which may assist elucidate that how tumor manipulate vessels growth to receive benefits. This study was published in PNAS.

Angiogenesis, the formation of new blood vessels from existing ones, is a vital process during embryonic development, homeostasis, and tumor progression. This process starts when cells release angiogenic growth factors such as VEGF in response to hypoxia.

The selection of the tip and the stalk cell fate is critical for developing a functional vessel. This decision is mediated by Notch signaling pathway (2), an evolutionarily conserved cell–cell communication pathway involved in cell fate decisions in multiple contexts. This pathway is activated when Notch (transmembrane receptor) belonging to a particular cell interacts with Delta or Jagged (transmembrane ligands) belonging to its neighboring cell (trans-activation), thereby releasing the Notch intracellular domain (NICD).

Developing effective antiangiogenesis strategies remains clinically challenging. Unlike physiological angiogenesis, pathological angiogenesis comprises of many microvessels that do not fully mature or develop functionally, because the cell fate decision about which endothelial cells become the tip and lead the following stalk cells is dysregulated.

In this study, scientists devised a specific theoretical framework to decipher the cross-talk between two crucial players of the decision-making process of tip and stalk cell fate: VEGF and Notch-Delta-Jagged signaling. They find that high expression of Jagged, but not Delta, can destabilize the terminal differentiation into tip or stalk cells and give rise to a hybrid tip/stalk phenotype, a phenotype that can transform physiological into pathological angiogenesis.

Their results offer insights into why tumor-stroma communication often implicates Jagged.

Researchers from The Wistar Institute have identified that sole use of inhibitors of PI3K in the cancer therapy may promote the metastasis to cause deterioration. This study was published in PNAS.

The phosphatidylinositol 3-kinase (PI3K) is a universal tumor driver that integrates growth factor signaling with downstream circuitries of cell proliferation, metabolism, and survival. Exploited in nearly every human tumor, including through acquisition of activating mutations, PI3K signaling is an important therapeutic target and several small-molecule antagonists of this pathway have entered clinical testing.

Despite the promise of personalized cancer medicine, most molecular therapies produce only modest and short-lived patient gains. In addition to drug resistance, it is also possible that tumors adaptively reprogram their signaling pathways to evade therapy-induced “stress” and, in the process, acquire more aggressive disease traits.

In this study, scientists show that small-molecule inhibitors of PI3K, a cancer node and important therapeutic target, induce transcriptional and signaling reprogramming in tumors. This involves the trafficking of energetically active mitochondria to subcellular sites of cell motility, where they provide a potent, “regional” energy source to support tumor cell invasion. Although this response may paradoxically increase the risk of metastasis during PI3K therapy, targeting mitochondrial reprogramming is feasible, and could provide a novel therapeutic strategy.