Stem cells, cancer progression and metastasis (part I) – Systemic instigation

by Alexey Bersenev on June 30, 2008 · 2 comments

in cancer, Journal club

So many publications have come up in the last few months, that may change our perception of the nature of cancer development, progression and metastatic process. Most of them discovered cellular mechanisms of cancer disease progression, involvement of cancer-initiating cells per se and different progenitor cell populations in bone marrow. In order to better understanding i decided to summarize some of conclusion and hypothesis that came from recent scientific papers. I’ll write a few short stories, combined under the common title “Stem cells, cancer progression and metastasis“. Today is part I – Systemic instigation. An idea to write this came up from inspiration from the lecture of Robert Weinberg, that was given June 10th at University of Pennsylvania.

The mechanisms of tumor outgrowth and metastasis and especially contribution of host systemic environment are poorly understood. Some studies had shown that host-derived bone marrow cells could make microenvironment and support tumor growth. A recent study from Whitehead Institute of MIT, published in Cell journal, described a new potential mechanism of systemic perturbation, leading to tumor growth facilitation – called “systemic instigation“.
The authors performed a series of elegant experiments which described this phenomenon, and identify a factors and mechanisms that caused it. The main conclusions from the paper are the following:

1 some primary tumors (breast carcinoma for instance) facilitate (instigate) growth of distant tumor-responders (indolent); instigation capacity is not unique (few cell lines have this ability) but not universal either;
2 profound instigation effect on tumor-responder is systemic but indirect and occurs due to functional perturbation of bone marrow (BM) by tumor-instigator with following requirement of BM cells into tumor-responder stroma;
3 perturbation of host bone marrow by instigator caused specific decreasing hematopoietic stem/progenitor cells compartment (LSK= Lin-/Sca1+/cKit+); the main population of bone marrow progenitors recruited to tumor-responder stroma are Sca1+/cKit-, which is also hematopoietic.
4 authors were lucky enough to figure out that the factor that causes systemic instigation effect is osteopontin (OPN); here I’d quote (i love this part of work):

There were no significant differences in the plasma levels of 80 distinct human cytokines in mice bearing instigating tumors compared with those bearing noninstigating tumors, with one exception: osteopontin (hOPN)

Inhibition of OPN abolished instigation ability;
5 systemic instigation is playing a role in metastatic process; OPN is necessary for the effect of primary instigating tumors on the outgrowth of lung metastases;

To summarize – some tumors can do kind of magic (on systemic level, – through release some factors into the blood) with bone marrow, progenitor populations in particular; this magic is called “instigation”; functionally perturbed bone marrow cells leave their niches and are mobilized into stroma of tumor-responder, that causes its growth and metastases.

” If metastases depend on stimulation by primary tumors, interception of the signal through neutralizing antibodies” might block cancer spread, said Robert Weinberg of the Massachusetts Institute of Technology. “That’s still speculative, but it’s an interesting idea to ponder”

6 systemic instigation effect could be used to study the growth and metastatic ability of some primary human tumors in serial transplant xeno-models; this application could solve the problem of some slow growing human tumors that was not possible to study before.

Still, the findings challenge the “prevailing view that primary tumors suppress the growth of derived metastases,” Weinberg said. “We argue they can foster cancer’s spread by activating bone marrow that is then recruited by distant metastases.
The findings also have important implications for the preclinical study of human cancers”, Weinberg emphasized.

In conclusion I’d like to say that identification of tumor-derived factors (additional to OPN) that functionally perturb systemic environment is important for understanding cancer progression and finding new specific targets for therapy.

2 things remain unclear for me (for discussion):

– how instigation occurred in clinic, where we have one primary tumor? Is it instigate itself? Or instigate micrometastases in bone marrow to mobilization?
– why did they indicate stromal precursors on the picture if paper indicated requirement of hematopoietic cells?

please feel free to discuss

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Cell, Vol 133, 994-1005, 13 June 2008
quotes from:
Primary Tumors Can Drive The Growth Of Distant Cancers (via Science Daily)

{ 1 comment… read it below or add one }

Denis July 3, 2008 at 11:39 am

“Instigation” – what does it mean?

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