Results of the self-study : a simple, but testable hypothesis…

Role of MicroRNA 210 in cancer drug resistance: Mechanism for a newpossible treatment strategy in cancer

The tumor microenvironment is a complex system of many cells, all of which participate in tumor progression, including epithelial cells, fibroblasts, infiltrating immune cells, structural components (extra cellular matrix) as well as secreted factors such as chemokines, cytokines and growth factors.

The interaction between the tumor cells and the surrounding cells—the microenvironment—helps drive the process of tumor progression, starting from normal to benign, benign to malignant and malignant to metastatic(ref). Fuelling further interests, two of the key characteristics of cancer are also dependent on the surrounding cells- the microenvironment, especially angiogenesis (creating the blood vessels that supply oxygen to the tumor), and invasion and metastasis (giving the tumor the ability to invade or travel to different parts of the body)(ref). Many cancers are characterized by the areas of hypoxia (i.e., low oxygen availability), which is a mark of rapidly proliferating tumors and has been suggested to be a characteristic of the embryonic and adult stem cell niche/microenvironment(ref). As hypoxia plays a critical role in early embryonic development and in tumor progression, including participating in processes such as cell migration, invasion and metastasis, angiogenesis and apoptosis, cancer cells in hypoxic areas of solid tumors are to a large extent protected against the action of radiation as well as many chemotherapeutic drugs (ref:).

MicroRNAs (miRs) are small, non-coding RNAs of 20-22 nucleotides involved in a wide variety of cellular processes(ref). Numerous studies have shown a link between hypoxia, a well-established component of the tumor microenvironment, and the miRs. One member of this class, miR-210, was identified as hypoxia inducible and is over-expressed in most cancers (ref). It has been demonstrated that the miR-210 modulates endothelial cell response to hypoxia and inhibits the receptor kinase ligand Ephrin-A3 (Eph-A3)(ref); however, no further progress has been made to better elucidate this new role and or its mechanisms. In this phase we would like to propose the following possible mechanism:

While miR-210 inhibits the Eph-A3, the ‘master regulator’ HIF regulates the proangiogenic function of miR210, within the complex cancer microenvironment. As a result of the regulation, neo-angiogenesis and vessel formation occur towards the development of a vascular niche. In the midst of this transformation, the Eph-A3, which is also expressed by a subset of tumors and/or possibly the cancer stem–cells (CSCs), may join together, along with the newly formed vascular niche. This is probably due to the high level of secretory molecules and further chemotaxis function (of the vascular niche itself). As a result of this newly formed, favourable CSCs-vascular niche complex, in addition to the hypoxia environment, the niche complexes may not only function as a regenerative cell pool of CSCs, but may also prevent the entry of chemotherapy drugs into the cancer cell. This would ultimately lead to the development of resistance to chemotherapy or radiotherapy, –- which is an increasing problem in the care of patients with cancer.

Nevertheless, while working on and confirming the hypothesis, we hope the area may also shed new light on the unanswered questions, such as the direct role of miR- 210 in CSCs and in the vascular niche complex, as well as its role in invasiveness and minimum residual disease.