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Trends in cancer stem cells – Interaction between stem cells and their niche in malignancy

Specific anatomical microenvironment or niche is a hallmark of adult somatic stem cell [1]. Based on the analogy, it was proposed that cancer stem cells (CSC) also have their niches [2]:

In either scenario, the CSC niches and the CSC entities are linked like an amniotic sack and a fetus; one cannot exist without the other.

But what are niches for cancer stem cells? We still have very little understanding of how tumor-initiating cells communicate with their environment. A few possible scenarios were proposed:

  1. Cancer stem cells create their own malignant niches directly (primary or metastatic site) or indirectly (via instigating bone marrow cells);
  2. Cancer stem cells can occupy existent normal stem cell niches directly (outcompete normal stem cells)
  3. Cancer stem cells hijack and modify normal niche cells, and make them abnormal.
  4. Transformation of niche cells is a primary event and development of cancer stem cells from normal cells residing in this niche is secondary.

I’ve summarized our current knowledge and added some interesting recent findings on this subject.

Cancer stem cells can create their own abnormal niches
Recently we have got few reports, suggested that cancer stem cells can make their own abnormal niches [3]. But all of these studies were done on a model of glioblastoma and their vascular niche. The significance of this phenomenon remains unclear for other types of malignant tumors.

Premetastatic niche formation as an initial event of metastasis
According to this hypothesis, metastatic cancer cells (stem- or non-stem is unclear) migrate into specific environment, prepared by instigated bone marrow cells [4]:

How particular tumor targets a particular metastatic site remains widely unknown. Nevertheless there are some indications to mechanisms how tumor-derived factors dictate metastatic patterns. Kaplan’s work showed [5], that after “tumor decides where”, signal molecules stimulate tissue-resident fibroblast-like stromal cells to produce fibronectin. It thus creates a “docking site” for arriving bone marrow cells, expressing integrins – receptors for fibronectin.

The role of cancer stem cells in formation of premetastatic niche remains unknown.

Metastatic cells from solid tumor can hijack normal stem cell niches
Russell Taichman’s group have found that normal hematopoitic stem cell niche in bone marrow could be hijacked by metastatic cancer cells [6]. Recently, they discussed the significance of this phenomenon in the review [7]:

It was recently found that prostate cancer (PCa) cells target the bone marrow microenvironment for HSCs, or HSC niche, during metastasis. Importantly, these disseminated PCa cells can be mobilized out of the niche using HSC mobilizing agents. These findings suggest that bone marrow HSC niche is a potential therapeutic target for metastatic disease.

Cancer stem cell outcompete normal stem cells for niche occupancy
This phenomenon was described in fruit flies [2]:

In Drosophila germaria, differentiation-defective hyperplastic stem cells outcompeted normal stem cells for occupancy of their niche. Those mutant stem cells exhibited upregulation of E-cadherin, an adherens junction receptor that mediates interaction between germinal stem cells and their niche.

In hematopoietic system, stem cells with mutations become fitter and outcompete normal stem cells for engraftment [8] in irradiated recipient:

So on one hand, loss of tumor-suppressor protect HSC from irradiation and give them “cellular mojo” – power to win competition for the niche and sustain hematopoiesis, on other hand this hematopoiesis could not be normal anymore. Selection for winners with low level or mutated tumor-suppressors will always lead to clonal expansion and domination (clonal evolution). These cells more definitely will be prone to acquisition of additional mutations and responsible for neoplastic process initiation.

Could transformed niche cells be contagious?
In other words, could transformed niche cells transfer malignant properties to normal stem cells? This is still a big open question, but there are some data suggesting that’s possible [9]:

The mechanisms of leukemogenesis from normal HSC after transplant is a black box. But it made us think about bone marrow niche-induce leukemogenesis as a possible cause.

David Scadden’s group showed that abnormal mesenchymal progenitors in bone marrow niche can promote leukemogenesis from normal HSC [10].

Could cancer stem cells be contagious?
Mickie Bhatia’s group in the recent study have demonstrated [11] that transformed human embryonic stem cell (t-hESC) are able to transfer “neoplastic properties” to normal hESC:

This transmission of neoplastic properties from t-hESCs to normal hESCs was dependent on direct cell–cell contact. Our study indicates that normal human stem cells can co-opt neoplastic cancer stem cell properties, raising the possibility that assimilation of healthy cells towards neoplastic behavior maybe a contributing feature of sustained tumorigenesis in vivo.

Despite the “killer title”, study didn’t provide solid evidence for ability of transformed ESC to transfer malignant properties to normal cells. For example, standard transplantation assays to prove carcinogenic properties, was not performed by authors. Nevertheless, the authors are proposing a very interesting concept and provide a good model, which could be explored further.

One of the potential mechanisms, which was dismissed in the Werbowetski-Ogilvie study [11], is a genetic material transfer by microvesicles [12]:

Recent publications show that glioblastoma cells release microvesicles that contain a select subset of cellular proteins and RNAs. These microvesicles are avidly taken up by normal cells in cell culture and can change the translational profile of these cells through delivery of tumor-derived mRNAs, which are translated into functional proteins. In addition to mRNA and proteins, microvesicles have been shown to contain microRNAs, non-coding RNAs and DNA.

The hypothesis of genetic material transfer from cancer stem cells into surrounding cells is very interesting and intriguing. Could it be a mechanism responsible for abnormalities in cancer stem cell niche?

The recent study [13] in renal cancer model showed that CSC can make a premetastatic niche via releasing of microvesicles:

Here we report that a subset of tumor initiating cells expressing the mesenchymal stem cell marker CD105 in human renal cell carcinoma release MVs that trigger angiogenesis and promote the formation of a pre-metastatic niche.

Unresolved questions:

  1. Do CSC create their own “malignant niches” or do they just hijack and modify already existent ones? Possibly, some malignant tumors can use both mechanisms in different stages of development.
  2. Is hijacking normal stem cell niches by malignant cells universal process or characterize only some tumors?
  3. How do primary tumor “choose” premetastatic site and “prepare the niche” before arrival of the first circulating tumor cell?
  4. Are cancer stem cell niches tumor-stage specific?
  5. Could neoplastic properties be transferred from CSC to their niche?
  6. Can primary neoplastic abnormalities in niche cells make cancer stem cells from normal stem cells?

This post is a part of series: Current Trends in Cancer Stem Cells [14]