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):
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!
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
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?