Limits...
Bone marrow microenvironment and tumor progression.

Chantrain CF, Feron O, Marbaix E, DeClerck YA - Cancer Microenviron (2008)

Bottom Line: First, the bone marrow actively recruits circulating tumor cells where they find a sanctuary rich in growth factors and cytokines that promote their proliferation and survival.The importance of this new knowledge cannot be underestimated considering that the vast majority of cancer treatments such as cytotoxic and myeloablative chemotherapy, bone marrow transplantation and radiation therapy inflict a trauma to the bone marrow microenvironment.How such trauma affects the influence that the bone marrow microenvironment exerts on cancer is still poorly understood.

View Article: PubMed Central - PubMed

Affiliation: Division of Hematology-Oncology, Department of Pediatrics, Universite Catholique de Louvain, Brussels, Belgium.

ABSTRACT
The bone marrow constitutes an unique microenvironment for cancer cells in three specific aspects. First, the bone marrow actively recruits circulating tumor cells where they find a sanctuary rich in growth factors and cytokines that promote their proliferation and survival. When in the bone marrow, tumor cells profoundly affect the homeostasis of the bone and the balance between osteogenesis and osteolysis. As a consequence, growth and survival factors normally sequestered into the bone matrix are released, further fueling cancer progression. Second, tumor cells actively recruit bone marrow-derived precursor cells into their own microenvironment. When in the tumors, these bone marrow-derived cells contribute to an inflammatory reaction and to the formation of the tumor vasculature. Third, bone marrow-derived cells can home in distant organs, where they form niches that attract circulating tumor cells. Our understanding of the contribution of the bone marrow microenvironment to cancer progression has therefore dramatically improved over the last few years. The importance of this new knowledge cannot be underestimated considering that the vast majority of cancer treatments such as cytotoxic and myeloablative chemotherapy, bone marrow transplantation and radiation therapy inflict a trauma to the bone marrow microenvironment. How such trauma affects the influence that the bone marrow microenvironment exerts on cancer is still poorly understood. In this article, the reciprocal relationship between the bone marrow microenvironment and tumor cells is reviewed, and its potential impact on cancer therapy is discussed.

No MeSH data available.


Related in: MedlinePlus

Revisiting the administration of high dose chemotherapy. a Recent observations suggest that there is an increase in the level of EPC after pulse high dose chemotherapy. This increase may favor tumor progression and the establishment of distant metastases if these cells are recruited by the primary tumor and by pre-metastatic niches. b The administration of agents blocking the recruitment of VEGFR-1 and 2 positive BMDC between courses of high dose chemotherapy may prevent a stimulation of neo-angiogenesis and the formation of pre-metastatic niche post chemotherapy
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2654350&req=5

Fig5: Revisiting the administration of high dose chemotherapy. a Recent observations suggest that there is an increase in the level of EPC after pulse high dose chemotherapy. This increase may favor tumor progression and the establishment of distant metastases if these cells are recruited by the primary tumor and by pre-metastatic niches. b The administration of agents blocking the recruitment of VEGFR-1 and 2 positive BMDC between courses of high dose chemotherapy may prevent a stimulation of neo-angiogenesis and the formation of pre-metastatic niche post chemotherapy

Mentions: It is now evident that the bone marrow plays a very unique microenvironmental role in carcinogenesis, tumorigenesis, angiogenesis and metastasis. Most of the experimental evidence discussed in this article suggests that it has a positive—and thus undesirable—effect on cancer progression. A major mechanism by which the bone marrow contributes to cancer progression is by the release of VEGFR-1 and VEGFR-2 precursor cells that are a source of mature inflammatory and vascular cells. The vast majority of the treatments currently used in human cancer, including high-dose cytotoxic and myeloablative chemotherapy, bone marrow transplantation and radiation therapy, cause an injury to the bone marrow that is followed by a phase of recovery. The effect of such injuries to the bone marrow microenvironment and in particular to the release of VEGFR-1 and -2 positive cells is so far poorly understood, but there is evidence that it may promote the release of these BMDC. For example, in animal models of limb injury the revascularization of the limb is accelerated if the mice receive low-dose irradiation, because irradiation of the bone marrow promotes the colonization of the injured limb by BMDC. Not surprisingly, this process is dependent on MMP-9 which increases the solubilization of Kit-L and the release of VEGF which both contribute to revascularization of the limb [104]. In mice treated with cyclophosphamide there is an increased release of EPC in the peripheral blood between 1 and 3 weeks after the administration of the cytotoxic agent. This release however is only observed if a bolus maximal tolerable dose is administered and not if low-dose metronomic doses are given [105, 106]. This thus supports the concept that high dose pulse chemotherapy may stimulate the release of EPC and ultimately tumor revascularization. In patients with cancer, studies have also shown an increase in EPC post high-dose chemotherapy [107]. However whether there is actually an increase in tumor vasculogenesis post administration of high-dose chemotherapy in human cancer has not been demonstrated yet. The data nevertheless suggest that pulses of high-dose chemotherapy may have an unanticipated and detrimental side effect by promoting the release of VEGFR-1 and -2 BMDC from the bone marrow osteoblastic niche into the peripheral blood circulation [108]. This may have several important and negative consequences on patient survival as it may not only promote inflammation and vasculogenesis in the primary tumor but also the formation of pre-metastatic niches and thus metastatic disease. Should this concept be correct, a better understanding of the mechanisms involved in the release of BMDC and how it is affected by injury to the bone marrow, will allow the design of new therapeutic protocols that could prevent the increased release of BMDC from the bone marrow niche (Fig. 5). For example, adding drugs that target VEGF, PlGF, SDF-1 or MMP-9 immediately after a pulse of high dose chemotherapy may prevent the release of VEGFR-1 and R2 positive cells from the bone marrow and their recruitment by the primary tumor or by pre-metastatic niches. A decrease in the levels of circulating EPC in patients with elevated VEGF levels in the peripheral blood (POEMS syndrome) treated with Bevasizumab (Avastin) has been recently shown [109]. MMP inhibitors have failed in clinical trials in the past but were tested in chronic administration in patients with end stage disease and with a reduction in the primary tumor as the therapeutic goal [110]. However when used for a short period of time between courses of intensive chemotherapy, they may be effective without unacceptable toxicity. Alternatively, intervening with SDF-1/CXCR-4 signaling with small inhibitors like AMD 3100 [111] may have a similar effect by preventing the colonization of the primary tumor by BMDC released into the peripheral blood post high-dose chemotherapy. There is clearly a fertile ground for investigation in this area that has the potential to significantly influence the way we administer chemotherapy to patients with cancer.Fig. 5


Bone marrow microenvironment and tumor progression.

Chantrain CF, Feron O, Marbaix E, DeClerck YA - Cancer Microenviron (2008)

Revisiting the administration of high dose chemotherapy. a Recent observations suggest that there is an increase in the level of EPC after pulse high dose chemotherapy. This increase may favor tumor progression and the establishment of distant metastases if these cells are recruited by the primary tumor and by pre-metastatic niches. b The administration of agents blocking the recruitment of VEGFR-1 and 2 positive BMDC between courses of high dose chemotherapy may prevent a stimulation of neo-angiogenesis and the formation of pre-metastatic niche post chemotherapy
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2654350&req=5

Fig5: Revisiting the administration of high dose chemotherapy. a Recent observations suggest that there is an increase in the level of EPC after pulse high dose chemotherapy. This increase may favor tumor progression and the establishment of distant metastases if these cells are recruited by the primary tumor and by pre-metastatic niches. b The administration of agents blocking the recruitment of VEGFR-1 and 2 positive BMDC between courses of high dose chemotherapy may prevent a stimulation of neo-angiogenesis and the formation of pre-metastatic niche post chemotherapy
Mentions: It is now evident that the bone marrow plays a very unique microenvironmental role in carcinogenesis, tumorigenesis, angiogenesis and metastasis. Most of the experimental evidence discussed in this article suggests that it has a positive—and thus undesirable—effect on cancer progression. A major mechanism by which the bone marrow contributes to cancer progression is by the release of VEGFR-1 and VEGFR-2 precursor cells that are a source of mature inflammatory and vascular cells. The vast majority of the treatments currently used in human cancer, including high-dose cytotoxic and myeloablative chemotherapy, bone marrow transplantation and radiation therapy, cause an injury to the bone marrow that is followed by a phase of recovery. The effect of such injuries to the bone marrow microenvironment and in particular to the release of VEGFR-1 and -2 positive cells is so far poorly understood, but there is evidence that it may promote the release of these BMDC. For example, in animal models of limb injury the revascularization of the limb is accelerated if the mice receive low-dose irradiation, because irradiation of the bone marrow promotes the colonization of the injured limb by BMDC. Not surprisingly, this process is dependent on MMP-9 which increases the solubilization of Kit-L and the release of VEGF which both contribute to revascularization of the limb [104]. In mice treated with cyclophosphamide there is an increased release of EPC in the peripheral blood between 1 and 3 weeks after the administration of the cytotoxic agent. This release however is only observed if a bolus maximal tolerable dose is administered and not if low-dose metronomic doses are given [105, 106]. This thus supports the concept that high dose pulse chemotherapy may stimulate the release of EPC and ultimately tumor revascularization. In patients with cancer, studies have also shown an increase in EPC post high-dose chemotherapy [107]. However whether there is actually an increase in tumor vasculogenesis post administration of high-dose chemotherapy in human cancer has not been demonstrated yet. The data nevertheless suggest that pulses of high-dose chemotherapy may have an unanticipated and detrimental side effect by promoting the release of VEGFR-1 and -2 BMDC from the bone marrow osteoblastic niche into the peripheral blood circulation [108]. This may have several important and negative consequences on patient survival as it may not only promote inflammation and vasculogenesis in the primary tumor but also the formation of pre-metastatic niches and thus metastatic disease. Should this concept be correct, a better understanding of the mechanisms involved in the release of BMDC and how it is affected by injury to the bone marrow, will allow the design of new therapeutic protocols that could prevent the increased release of BMDC from the bone marrow niche (Fig. 5). For example, adding drugs that target VEGF, PlGF, SDF-1 or MMP-9 immediately after a pulse of high dose chemotherapy may prevent the release of VEGFR-1 and R2 positive cells from the bone marrow and their recruitment by the primary tumor or by pre-metastatic niches. A decrease in the levels of circulating EPC in patients with elevated VEGF levels in the peripheral blood (POEMS syndrome) treated with Bevasizumab (Avastin) has been recently shown [109]. MMP inhibitors have failed in clinical trials in the past but were tested in chronic administration in patients with end stage disease and with a reduction in the primary tumor as the therapeutic goal [110]. However when used for a short period of time between courses of intensive chemotherapy, they may be effective without unacceptable toxicity. Alternatively, intervening with SDF-1/CXCR-4 signaling with small inhibitors like AMD 3100 [111] may have a similar effect by preventing the colonization of the primary tumor by BMDC released into the peripheral blood post high-dose chemotherapy. There is clearly a fertile ground for investigation in this area that has the potential to significantly influence the way we administer chemotherapy to patients with cancer.Fig. 5

Bottom Line: First, the bone marrow actively recruits circulating tumor cells where they find a sanctuary rich in growth factors and cytokines that promote their proliferation and survival.The importance of this new knowledge cannot be underestimated considering that the vast majority of cancer treatments such as cytotoxic and myeloablative chemotherapy, bone marrow transplantation and radiation therapy inflict a trauma to the bone marrow microenvironment.How such trauma affects the influence that the bone marrow microenvironment exerts on cancer is still poorly understood.

View Article: PubMed Central - PubMed

Affiliation: Division of Hematology-Oncology, Department of Pediatrics, Universite Catholique de Louvain, Brussels, Belgium.

ABSTRACT
The bone marrow constitutes an unique microenvironment for cancer cells in three specific aspects. First, the bone marrow actively recruits circulating tumor cells where they find a sanctuary rich in growth factors and cytokines that promote their proliferation and survival. When in the bone marrow, tumor cells profoundly affect the homeostasis of the bone and the balance between osteogenesis and osteolysis. As a consequence, growth and survival factors normally sequestered into the bone matrix are released, further fueling cancer progression. Second, tumor cells actively recruit bone marrow-derived precursor cells into their own microenvironment. When in the tumors, these bone marrow-derived cells contribute to an inflammatory reaction and to the formation of the tumor vasculature. Third, bone marrow-derived cells can home in distant organs, where they form niches that attract circulating tumor cells. Our understanding of the contribution of the bone marrow microenvironment to cancer progression has therefore dramatically improved over the last few years. The importance of this new knowledge cannot be underestimated considering that the vast majority of cancer treatments such as cytotoxic and myeloablative chemotherapy, bone marrow transplantation and radiation therapy inflict a trauma to the bone marrow microenvironment. How such trauma affects the influence that the bone marrow microenvironment exerts on cancer is still poorly understood. In this article, the reciprocal relationship between the bone marrow microenvironment and tumor cells is reviewed, and its potential impact on cancer therapy is discussed.

No MeSH data available.


Related in: MedlinePlus