The discovery that cancer cells discharge vast quantities of extracellular vesicles (EVs), underscored the explosion of the EV field. A large body of evidence now supports their onco-functionality in an array of contexts; stromal crosstalk, immune evasion, metastatic site priming, and drug resistance - justifying therapeutic intervention. The current bottleneck is a lack of clear understanding of why and how EV biogenesis ramps up in cancer cells, and hence where exactly avenues for intervention may reside. We know that EVs also play an array of physiological roles, therefore effective anticancer inhibition requires a target distinct enough from physiology to achieve efficacy. Taking the perspective that EV upregulation may be a consequence of the tumor landscape, we examine classic mutational events and tumor characteristics for EV regulators. All the while, aiming to illuminate topics worth further research in therapeutic development.

The insulin-like growth factor type 1 receptor (IGF-1R) plays a key role in the development and maintenance of cancer. Since the first links between growth factor receptors and oncogenes were noted over three decades ago, targeting the IGF-1R has been of great interest. This review follows the progress from inception through intense pharmaceutical development, disappointing clinical trials and recent updates to the signaling paradigm. In light of major developments in signaling understanding and activation complexities, we examine reasons for failure of first line targeting approaches. Recent findings include the fact that the IGF-1R can signal in the absence of the ligand, in the absence of kinase activity and utilizes components of the GPCR system. With recognition of the unappreciated complexities that this first wave of targeting approaches encountered, we advocate recognition of IGF-1R as a valid target for cancer treatment and look to future directions, where both research and pharmaceutical strengths can lend themselves to finally unearthing anti-IGF-1R potential.

Ligand-activated plasma membrane receptors follow pathways of endocytosis through the endosomal sorting apparatus. Receptors cluster in clathrin-coated pits that bud inwards and enter the cell as clathrin-coated vesicles. These vesicles travel through the acidic endosome whereby receptors and ligands are sorted to be either recycled or degraded. The traditional paradigm postulated that the endocytosis role lay in signal termination through the removal of the receptor from the cell surface. It is now becoming clear that the internalization process governs more than receptor signal cessation and instead reigns over the entire spatial and temporal wiring of receptor signaling. Governing the localization, the post-translational modifications, and the scaffolding of receptors and downstream signal components established the endosomal platform as the master regulator of receptor function. Confinement of components within or between distinct organelles means that the endosome instructs the cell on how to interpret and translate the signal emanating from any given receptor complex into biological effects. This review explores this emerging paradigm with respect to the cancer-relevant insulin-like growth factor type 1 receptor (IGF-1R) and discusses how this perspective could inform future targeting strategies.