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.

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

Secreted factor Lefty: a novel marker to identify modified hESC niches/
microenvironments

Human Embryonic Stem-Cells (hESCs) provide an opportunity for modelling
human-specific strategies in order to study the earliest molecular events leading to
normal haematopoietic specification versus leukaemia transformation. Although the
profound influence of the stroma on tumorogenesis is now widely accepted, a full
understanding of the crosstalk between stem cells and the niche, and the role of the
stem-cell niche on the development of leukaemia stem-cells (LSCs) and cancer stemcells
(CSCs), are in their earliest stage of research. On the other hand, though much
of active research is focusing mainly on the identification of novel markers for cancer
stem-cells in order to offer new therapeutic strategies to inhibit tumor progression,
the differentiating molecular events that transform normal hESCs into leukaemia
formations is still obscure. In this scenario, there is an urgency to find a simple and
novel secreted molecule and/or morphogen that could help us to identify the earliest
molecular events that transform normal hESCs into leukaemia cells.

In normal adult tissues, paracrine signals that derive from the stem cell niche, or
microenvironment, play an important role in regulating the critical balance between
activity and quiescence of stem cells. Similarly, evidence has emerged to support the
hypothesis that signals derived from the microenvironment regulate cancer cells in
an analogous manner. The stem-cell-associated factors include members of the
Notch, Wingless, and the transformation growth factor beta (TGF-B) super family
such as the teratoma-derived growth factor-1 (TDGF-1/Cripto, which is an EGF-CFC
co-receptor for Nodal signalling) and Lefty (inhibitor of Nodal signalling). Recently,
it has been demonstrated that the exposure of the tumor cells to a hESCs
microenvironment (containing Lefty, which is exclusive to the hESCs) leads to
dramatic down-regulation of the Nodal expression in aggressive tumor cells,
concomitant with a reduction in clonogenicity and tumorigenesis (with apoptosis).

The anti-tumorigeneic potential of Lefty is secreted into the hESCs
microenvironment and exemplifies the tumor suppressive effects of the hESCs
microenvironment. This effect is exclusive to hESCs and not other stem cell types
derived from amniotic fluid, cord blood, or adult bone marrow.

The different and unique qualities of the Lefty protein suggest that it could serve as a
novel marker towards differentiation between normal and transformed or modified
hESCs.

Furthermore, while confirming the hypothesis, we hope this interdisciplinary
research may also shed new light onto other key aspects, such as any Lefty protein
pathway crosstalk in the modified hESCs, and also improved understanding of their
complete feedback signalling networks and their suppressive regulative functions in
the adult cancerous cells.

References:
[1] P Catalina, etal., Genetic stability of human embryonic stem cells: A first-step
toward the development of potential hESC-based systems for modeling childhood
leukemia, Leuk Res 33 (2009), pp.980-90.
[2] JB Sneddon, The contribution of niche-derived factors to the regulation of cancer
cells, Methods Mol Biol 568 (2009), pp. 217-32.
[3] D Besser, Expression of nodal, lefty-a, and lefty-B in undifferentiated human
embryonic stem cells requires activation of Smad2/3, J Biol Chem 279 (2004), pp.
45076-84.
[4] LM Postovit etal., Human embryonic stem cell microenvironment suppresses the
tumorigenic phenotype of aggressive cancer cells, Proc Natl Acad Sci U S A 105
(2008), pp. 4329-34.

multiple role of a transcription factor : connecting metastasis and stem-cell niche/microenvironment ..

Development of hematopoietic stem cells (HSC) and their immediate progeny is maintained by the interaction with cells in the microenvironment. But how the transcription factors involve to regulate the hematopoietic progenitor cell niche was remains unclear. In this phase, Suh etal have demontsrated the cell non-autonomous function of Id1 in the hematopoietic progenitor cell niche by using the knock-out mouse model. Here one practical tip is that Id1-/- stromal cells showed altered production of cytokines in vitro as well as the cytokine levels were deregulated in vivo, which could responsible for the Id1-/- hematopoietic phenotypes. Furthermore, the research group are also adding further more enthusiasms by utilising the ID genes families, which function is required for the mobilization of endothelial precursor cells from the bone marrow during the pathological tumor angiogenesis, and the expression of these genes remains high in tumor vasculature ( Shaked Y etal in Science 2006 and Lyden etal in Nature 1999). Here there is an another interesting point; that one is (continue below.!)

Two years ago…

the same gene has also been shown to mediates tumor reinitiation during breast cancer lung metastasis, which was done by Joan Massague

Nevertheless, the whole concepts were also developing number of curiosity questions as well such as: are there any relationship between ID genes and pre-metastatic niche?
does the altered production of the cytokines has any role with the quiescent stem- cells? Does the ID genes also play any role to establish the ‘cancer stem-cell niche’? if the ID genes does role on tumor reinitiation means does it also play any role for modifying and or creating the tumor (favourable) microenvironment? …!

Role of oncogenic K-ras

A subset of neoplastic cells , in the cancer stem-cells niche/microenvironment, has features that not only sustain glioma growth but may also confer resistance to standard glioma treatments. At the very basic level, however, whether glioma stem cells derive from indigenous neural stem cells (NSC), or from tumor cells that have reacquired stem cell-like properties, is still unknown. In this thrilling phase, report from Moses group demonstrating in vivo that the infiltrating tumor cells may arise from NSC transformed by activation of oncogenic K-ras.

One Year Ago….:

In medulloblastoma, Hambardzumyan and colleagues demonstrated in vivo that PI3K signaling pathway regulates survival of cancer stem cells residing in the perivascular niche following the radiation

up-dating the niche model

According to the osteoblastic niche model, which was originally proposed by Scadden and Linheng Li, the hematopoietic stem cells (HSCs) are maintained by the junction protein called N-cadherin-mediated homophilic adhesion to osteoblasts at the bone marrow endosteum. In contrast to this model, recent report from Sean Morrison group demonstrating that the N-cadherin expression by HSCs is not necessary for niche function. Extending this surprise results they have also demonstrated that N-cadherin deficiency did not affect bone marrow cellularity or lineage composition, the numbers of colony-forming progenitors, the frequency of HSCs, the ability of HSCs to sustain hematopoiesis over time, or their ability to reconstitute irradiated mice in primary or secondary transplants. This is quite interesting reports.

One Year Ago….:

Linheng Li and colleagues reveal differential N-cadherin expression reflects functional distinctions between two HSC subpopulations i.e., reserved versus primed states of hematopoietic stem cells.

a paper from the EuroSTELLS workshop....

here is an article from the 'EuroSTELLS Workshop -Stem Cell Niches', superbly written by Prof. Dr. Elaine Dzierzak and Tariq Enver.

PS: if the above link doe'snt work or doesnt open the article means then please follow the link:
click here , then come to the second paragraphs (...Read a meeting review of the workshop in Development...and click the link..!)

for a summary / abstract : please click here