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

Novel approaches to identify target genes for metastasis and pre-metastatic niche, within the context of cancer stem-cell niche /microenvironment

Physician Stephen Paget's 1889 proposal still holds forth today that metastasis is a multistage process that requires intravasated cancer cells to escape from the primary tumors (the ‘seeds’), survive in the circulation, arrive at the target or specific organ microenvironments and grow (the ‘soil’). Each of these stages is inefficient and some of them are rate-limiting steps that are supported by the functions of the cancer cells themselves, the tumor stroma the tumor microenvironment. Recently, a number of reports have highlighted that the embryonic microenvironment clearly suppresses the malignancy of potentially metastatic cells (ref.) nevertheless, the steps to re-activation that forms a clinically relevant metastasis probably occur through perturbations in the microenvironment.

A great deal of evidence increasingly supports the role of the tumor microenvironment in the development of cancer metastasis, but there currently is no proof of a correlation at the level of the role of cell surface microenvironments in the modulation of receptor signaling. This is probably due to the very complex nature of cancer microenvironments. In order to translate the basic research and help to augment the number of cancer survivors, we would, therefore, like to suggest the following solution in order to identify novel target genes:

First step: list the genes that are initiating the tumor functions; such as oncogenes (EGFR, ERBB2, cMYC, CTNNB1 (beta-catenin), KRAS, PI3K), tumor suppressors (APC, BRCA1, BRAC2, TP53, and PTEN);Second step: list the genes that are causing the metastatic functions (gain of functions such as ID1, MET, SNAI, SNAI2, as well as loss of functions such as DARC, GPR56, KISS1);The third step: list the genes that are responsible for metastatic progression; such as ANGPTL4, CCL5, EREG, LOX, MMP1, and PTGS2;The final step is to list the genes that cause the metastatic virulence functions such as IL6, IL11, and CSF2RB (GM-CSF), PTHRP, TNF-alpha.

After the above listings and/or the preparative steps, we will begin to modulate the genes and their signaling pathways (EGFR, for example) in each step and study their effects on the cell surface microenvironment. Since the cancer stem-cell niche/microenvironment plays a fundamental and important role in spreading the cancer cells, we hope that beginning with a basic approach will not only give us opportunities to identify novel target genes which could define the interactions between the cancer cells and the microenvironment, but may also, due to the altered properties of cancer stem-cell niches/microenvironments, create opportunities to study how these genes and their signaling pathways contribute to metastasis, pre-metastatic niche, etc. Furthermore, since abnormal cell signaling pathways are a hallmark of cancer cells, discovering how they interact with each other could also offer further important clues as to how to halt tumor cell division, survival, or metastasis.

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.