Stem cells, cancer progression and metastasis (part III) – premetastatic niche

by Alexey Bersenev on March 18, 2009 · 5 comments

in cancer, migration, niche

I continue to collect and share some theories about involvement of bone marrow cells in tumor progression and metastasis. Last year I summarized some knowledge in 2 parts: I – systemic instigation and II – angiogenesis. Going to get into it more this year. Today my story is about premetastatic niche.

Emerging evidence suggests that certain primary tumour cells release soluble factors that induce a specific population of non-malignant haematopoietic cells to mobilize and engraft distant organ tissues, thereby establishing a ‘premetastatic niche’ that lay a foundation for incoming circulating cancer cells.
(Rosandra N. Kaplan, Shahin Rafii and David Lyden)

Here we discuss a lot about bone marrow niches for hematopoietic stem cells, but what is the so-called premetastatic niche? It is a specific microenvironment that allows malignant cells to migrate from primary tumor and develop metastasis. I’d like to distinguish the premetastatic niche from the cancer stem cell niche, which is characterized by steady-state tumor and doesn’t necessarily require bone marrow cell involvement.

Niche-to-niche migration of BM and tumor cells (credit: Jared Wels, 2008):

Most of the work described below was done in the labs of Shahin Rafii and David Lyden (Weil Cornell Medical College and Memorial Sloan-Kettering Cancer Center, New York).

As far as I was able to track, the first study described in detail how bone marrow cells make the niche for cancer metastasis, which was done by Rosandra Kaplan and collegues in 2005. They described the process of migration of VEGFR1+ bone marrow-derived haematopoietic progenitor cells to tumor-specific pre-metastatic sites and form special environment before the arrival of tumor cells.

In order to define and study the pre-metastatic niche researchers trying to answer to some following questions:

what the earliest event in metastatic site?
The first magic that cancer does with the body:

… the primary tumor cell with its production of a unique array of tumor chemokines that orchestrates formation of the premetastatic niche and specifically dictates the pattern of tumor spread.

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, 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.

Later on Hiratsuka and colleagues showed that:

Primary tumors release soluble factors, including VEGF-A, TGFβ and TNFα, which induce expression of the chemokines S100A8 and S100A9 in the myeloid and endothelial cells within the lung before tumour metastasis.

what signals and molecules orchestrate bone marrow cell migration into a specific metastatic site? is it a direct or indirect process?

In Kaplan’s experiments melanoma cells had secreted some factors that mobilized the bone marrow cells into specific site – the lungs. They showed that it’s an indirect process and proliferating cellular clusters in targeted organ attract bone marrow progenitors. Migrated VEGFR1+ progenitors provide adhesion molecules (VLA-4, Id3), proteinases (MMP9), chemokines (SDF-1) and growth factors in order to attract cancer cells and more progenitors from bone marrow (including endothelial).

In her review Rosandra Kaplan noticed that a tumor can stimulate migration of bone marrow cells simulteneously with begining of fibronectin production in site of “cellular bookmark”:

Nearly all tumors produce high levels of VEGF, with fewer cancers synthesizing both VEGF and placental growth factor (PlGF). PlGF/VEGF–derived tumors tend to mobilize and recruit more VEGFR1-expressing cells with resultant-enhanced HPC clustering and metastasis at multiple sites.

Recently discovered are yet another set of molecules, such as lysyl oxidase (LOX), released by primary tumors and acting on distant fibroblasts in “metastatic bookmark”.

which population of bone marrow cells migrate in order to make “a bed for metastatic cancer”?

The first investigated population was VEGFR1+ hematopoietic progenitors. Proliferation of these cells and production of signaling molecules attract other bone marrow cells – endothelial progenitors and mesenchymal stromal cells in order to make a vasculature and stroma for future metastasis.

LOX expression in the premetastatic niche attract CD11b+ myeloid progenitors first, before starting the cascade of signals and involving more bone marrow cells.

how can we manipulate the premetastatic niche in therapeutic settings?

All the studies I cited here used some therapeutic approaches based on premetastatic niche manipulation. Kaplan and colleagues demonstrated prevention of premetastatic niche formation by administration of antibody to VEGFR1. Hiratsuka showed that antibodies against S100A8 and S100A9 dramatically reduced migration of tumor cells to metastatic site (lungs). Finally, Erler with colleagues showed LOX inhibition prevents CD11b+ cell recruitment and metastatic growth.

You could think that everything described here is reminiscent of the process of systemic instigation, but:

This mechanism requires seeded metastatic cells and long periods of incubation, and so it is functionally distinct from the pre-metastatic niche concept.

In the recent review “Microenvironmental regulation of metastasis“, the authors described in detail the involvement of all different kinds of bone marrow cells in cancer progression and metastasis and current status of “seed and soil” concept (Paget, 1889). Highly recommend reading this!
read more:

free reviews (OA):
Rosandra N. Kaplan, Shahin Rafii and David Lyden. Preparing the “Soil”: The Premetastatic Niche. Cancer Res 2006; 66: 11089
Jared Wels, Rosandra N. Kaplan, Shahin Rafii and David Lyden. Migratory neighbors and distant invaders: tumor-associated niche cells. Genes & Dev 2008; 22:559

Shahin Rafii & David Lyden. S100 chemokines mediate bookmarking of premetastatic niches. Nat Cell Biol 2006;8:1321
Patricia S. Steeg. Emissaries set up new sites. Nature 2005;438:750

related posts:
Stem cells, cancer progression and metastasis (part I) – Systemic instigation
Stem cells, cancer progression and metastasis (part II) – angiogenesis
How do traveling normal and malignant cells decide where to stay? Lessons from mammary cells
Pathotropism – what mediate stem cell tropism to tumor?

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{ 5 comments… read them below or add one }

Lei March 18, 2009 at 8:00 pm

The question is “why” bone marrow stromal cells help to prepare a nursery for cancer cell. If cancer cells are more evoluted and can make everybody work for their benefic and the result is the death of the host, what is Darwinism all about?


JWS March 18, 2009 at 8:28 pm

It actually makes sense because cancer cells may actually evolve to win over normal physiology – that’s why we need treatment to counter against it. If Darwinism is correct, we will eventually acquire ability to counter cancer cells over time, but not immediately – maybe treatment that human beings come up with from their imagination and creativity will allow ourselves to evolve….


m@w March 19, 2009 at 1:25 am

good point about the Darwinism…but the opposite case is also possible according to the theory of artificial selection…since our professional activities allow patients with highly malignant tumors and leukemias survive and leave progeny, there is a “breeding” of predisposed population


Alex March 19, 2009 at 1:52 am

to Lei –
“why stromal cells prepare the bed?”
they don’t really care where to go because of chemotaxis, any place in our body where there is a signals noise (such as SDF-1, HIF, fibronectin ect.) they will go and do their job. It’s could be good if it’s damaged organ reparation (we can call them smart) or could be bed if it’s cancer makes them to do so (we can call them stupid).
That’s why stem cells injections with a purpose of repair damaged organ is always risky if we have a tumor hiding somewhere in the body.


Lei March 19, 2009 at 10:14 pm

Given the fact that our body produces 1M mutated cells everyday, the “preparation of the bed” theory is scary.
Then we come up with the delimma proposed by m@w, active pharmacological intervention leads to the disruption of “natural” selection; on the other hand, leaving sick patients behind is obviously immoral.
Anyways, like Alex said, we can just play with “cancer”, “stem cell”, “individualized therapeutic” concepts and get grant money.


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