Missed Druggable Cancer Hallmark: Cancer–Stroma Symbiotic Crosstalk as Paradigm and Hypothesis for Cancer Therapy

Abstract

During tumor evolution, cancer cells use the tumor-stroma crosstalk to reorganize the microenvironment for maximum robustness of the tumor. The success of immune checkpoint therapy foretells a new cancer therapy paradigm: an effective cancer treatment should not aim to influence the individual components of super complex intracellular interactomes (molecular targeting), but try to disrupt the intercellular interactions between cancer and stromal cells, thus breaking the tumor as a whole. Arguments are provided in favor of a hypothesis that such interactions include formation of synapse-like structures (interfaces) where the interacting cells are located at a distance of ∼10-15 nm. Within these interfaces, molecules initiating and strengthening the interaction are organized, and allow optimum cross-signaling; a very confined intercellular space facilitates the concentration of secreted cytokines, enhancing the paracrine cross-communication. These features of tumors form a druggable cancer hallmark the tumor-stroma symbiotic crosstalk-which represents a new target for efficient cancer drug discovery.

<p>PDX1, a key factor in pancreatic embryogenesis, can exhibit antimetastatic activity in pancreatic ductal adenocarcinoma</p>

“…Another key determinant in cancer development and metastasis is the tumor microenvironment (for a recent review, see11). In particular, cancer-associated fibroblasts (CAFs) are often found in the vicinity of or in direct contact with neoplastic cells and can co-travel in the blood with circulating murine metastatic lung carcinoma cancer cells, probably supporting the cancer cell viability and growth advantage at the metastatic site.…”

Are Synapse-Like Structures a Possible Way for Crosstalk of Cancer with Its Microenvironment?

“…The non-cellular component is represented by the extracellular matrix [26][27][28]. Cancer and stromal components form an integrated and evolving system with multiple interactions and emergent properties [26,[29][30][31][32]. In their evolution, all tumors use a wide repertoire of healthy cells and adapt them to their conditions.…”

“…Generally, this paradigm focuses on interactions between cancer and the stromal cells as therapeutic targets. It was suggested [30], that only direct interactions (for example, between ligands and their cognate receptors) form relatively simple binary contacts that are necessary for…”

Inhibitor-conjugated harmonic nanoparticles targeting fibroblast activation protein

“…22,23 The tumor-stroma symbiotic cross-talk was even proposed as a new cancer hallmark by Sverdlov in 2018. 24 A specic characteristic of CAFs is the expression of broblast activation protein a (FAP), a transmembrane protease which is not found in normal, healthy adult tissues, except in granulation tissue of healing wounds. [25][26][27] However, the mechanisms underlying the physiological and pathological functions of FAP are not fully elucidated.…”