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Role of cancer microenvironment in metastasis: focus on colon cancer.

Gout S, Huot J - Cancer Microenviron (2008)

Bottom Line: In most cases, death will result from the formation of distal secondary sites called metastases.These mutations lead to unrestrained growth of the primary neoplasm and a propensity to detach and to progress through the subsequent steps of metastatic dissemination.This process depends tightly on the surrounding microenvironment.

View Article: PubMed Central - PubMed

Affiliation: Le Centre de recherche en cancérologie de l'Université Laval, L'Hôtel-Dieu de Québec, 9 rue McMahon, Quebec, Canada.

ABSTRACT
One person on three will receive a diagnostic of cancer during his life. About one third of them will die of the disease. In most cases, death will result from the formation of distal secondary sites called metastases. Several events that lead to cancer are under genetic control. In particular, cancer initiation is tightly associated with specific mutations that affect proto-oncogenes and tumour suppressor genes. These mutations lead to unrestrained growth of the primary neoplasm and a propensity to detach and to progress through the subsequent steps of metastatic dissemination. This process depends tightly on the surrounding microenvironment. In fact, several studies support the point that tumour development relies on a continuous cross-talk between cancer cells and their cellular and extracellular microenvironments. This signaling cross-talk is mediated by transmembrane receptors expressed on cancer cells and stromal cells. The aim of this manuscript is to review how the cancer microenvironment influences the journey of a metastatic cell taking liver invasion by colorectal cancer cells as a model.

No MeSH data available.


Related in: MedlinePlus

The journey of a metastatic cell: from the primary site to the secondary site. Cancer cells have a “long and difficult” journey to go on before colonizing a secondary site and form metastases. This journey comprises several milestones that are summarized as follows: a Proliferation of primary tumour, b Local invasion of detached cells. c Intravasation in a capillary, and tumour cell survival in blood circulation: 1, interaction with leukocytes that may be destructive or not; 2, aggregation with platelets, which protects cancer cells against mechanical stress and leukocytes; 3, tumour cell–cell aggregation, which protects against stress and formation of intra capillary thrombosis. d Arrest and extravasation in a target organ. e Metastatic growth in the new appropriate environment and formation of a secondary neoplasm
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Fig6: The journey of a metastatic cell: from the primary site to the secondary site. Cancer cells have a “long and difficult” journey to go on before colonizing a secondary site and form metastases. This journey comprises several milestones that are summarized as follows: a Proliferation of primary tumour, b Local invasion of detached cells. c Intravasation in a capillary, and tumour cell survival in blood circulation: 1, interaction with leukocytes that may be destructive or not; 2, aggregation with platelets, which protects cancer cells against mechanical stress and leukocytes; 3, tumour cell–cell aggregation, which protects against stress and formation of intra capillary thrombosis. d Arrest and extravasation in a target organ. e Metastatic growth in the new appropriate environment and formation of a secondary neoplasm

Mentions: The journey of colon cancer cells from the primary site to the secondary sites is paved by obstacles that render the process destructive and ineffective (Fig. 6). Yet, some cells succeed and traverse all these impediments to generate metastases that will become fatal. In each case, the molecular events that lead to the massive destruction of the cancer cells or allow their survival during their journey is governed by an intricate interacting cross-talk between the cancer cells and its microenvironment. We have briefly reviewed some of these molecular interactions that characterize the journey of colon cancer cells to the liver. Much remains to be elucidated to fully understand the whole process. Nevertheless, little by little our knowledge increases, which contributes to improve our therapeutic intervention. The discovery that the anti-VEGF monoclonal antibody bevacuzimab increases the survival of colon cancer patient by impairing angiogenesis is one the best example. In fact, any therapy that interferes with the interaction of cancer cells with its microenvironment has promising clinical outcome. For example, one may envision targeting CAFs, EMT or MET as therapeutic purposes. Targeting the growth of metastases at the secondary site is particularly attractive since this event occurs often before the clinical detection of the primary neoplasm. In this context, components of the TGFβ pathway, a major player of EMT, are considered to be important new therapeutic targets. In line with this, new inhibitors of this pathway are already being tested in pre-clinical and clinical trials. Notably, four main strategies have been designed for disrupting TGFβ signaling: inhibition or sequestration of TGFβ, inhibition of TGFβ receptor kinase activity, inhibition of SMAD signaling downstream of TGFβ and restoration of anti-tumour immunity upon TGFβ inhibition [148]. In this regard, an antisense-based therapy against TGF-β2 is presently in a phase I/II study investigating treatment of colorectal cancer [149]. Moreover, approaches to increase immunosurveillance are under investigation and should lead to important therapeutic breakthroughs. Accordingly, interesting results have been obtained in mice using dendritic cell vaccination [150]. In our opinion, we believe that the next few years will be more fruitful in identifying new therapeutic targets in this direction.Fig. 6


Role of cancer microenvironment in metastasis: focus on colon cancer.

Gout S, Huot J - Cancer Microenviron (2008)

The journey of a metastatic cell: from the primary site to the secondary site. Cancer cells have a “long and difficult” journey to go on before colonizing a secondary site and form metastases. This journey comprises several milestones that are summarized as follows: a Proliferation of primary tumour, b Local invasion of detached cells. c Intravasation in a capillary, and tumour cell survival in blood circulation: 1, interaction with leukocytes that may be destructive or not; 2, aggregation with platelets, which protects cancer cells against mechanical stress and leukocytes; 3, tumour cell–cell aggregation, which protects against stress and formation of intra capillary thrombosis. d Arrest and extravasation in a target organ. e Metastatic growth in the new appropriate environment and formation of a secondary neoplasm
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2654352&req=5

Fig6: The journey of a metastatic cell: from the primary site to the secondary site. Cancer cells have a “long and difficult” journey to go on before colonizing a secondary site and form metastases. This journey comprises several milestones that are summarized as follows: a Proliferation of primary tumour, b Local invasion of detached cells. c Intravasation in a capillary, and tumour cell survival in blood circulation: 1, interaction with leukocytes that may be destructive or not; 2, aggregation with platelets, which protects cancer cells against mechanical stress and leukocytes; 3, tumour cell–cell aggregation, which protects against stress and formation of intra capillary thrombosis. d Arrest and extravasation in a target organ. e Metastatic growth in the new appropriate environment and formation of a secondary neoplasm
Mentions: The journey of colon cancer cells from the primary site to the secondary sites is paved by obstacles that render the process destructive and ineffective (Fig. 6). Yet, some cells succeed and traverse all these impediments to generate metastases that will become fatal. In each case, the molecular events that lead to the massive destruction of the cancer cells or allow their survival during their journey is governed by an intricate interacting cross-talk between the cancer cells and its microenvironment. We have briefly reviewed some of these molecular interactions that characterize the journey of colon cancer cells to the liver. Much remains to be elucidated to fully understand the whole process. Nevertheless, little by little our knowledge increases, which contributes to improve our therapeutic intervention. The discovery that the anti-VEGF monoclonal antibody bevacuzimab increases the survival of colon cancer patient by impairing angiogenesis is one the best example. In fact, any therapy that interferes with the interaction of cancer cells with its microenvironment has promising clinical outcome. For example, one may envision targeting CAFs, EMT or MET as therapeutic purposes. Targeting the growth of metastases at the secondary site is particularly attractive since this event occurs often before the clinical detection of the primary neoplasm. In this context, components of the TGFβ pathway, a major player of EMT, are considered to be important new therapeutic targets. In line with this, new inhibitors of this pathway are already being tested in pre-clinical and clinical trials. Notably, four main strategies have been designed for disrupting TGFβ signaling: inhibition or sequestration of TGFβ, inhibition of TGFβ receptor kinase activity, inhibition of SMAD signaling downstream of TGFβ and restoration of anti-tumour immunity upon TGFβ inhibition [148]. In this regard, an antisense-based therapy against TGF-β2 is presently in a phase I/II study investigating treatment of colorectal cancer [149]. Moreover, approaches to increase immunosurveillance are under investigation and should lead to important therapeutic breakthroughs. Accordingly, interesting results have been obtained in mice using dendritic cell vaccination [150]. In our opinion, we believe that the next few years will be more fruitful in identifying new therapeutic targets in this direction.Fig. 6

Bottom Line: In most cases, death will result from the formation of distal secondary sites called metastases.These mutations lead to unrestrained growth of the primary neoplasm and a propensity to detach and to progress through the subsequent steps of metastatic dissemination.This process depends tightly on the surrounding microenvironment.

View Article: PubMed Central - PubMed

Affiliation: Le Centre de recherche en cancérologie de l'Université Laval, L'Hôtel-Dieu de Québec, 9 rue McMahon, Quebec, Canada.

ABSTRACT
One person on three will receive a diagnostic of cancer during his life. About one third of them will die of the disease. In most cases, death will result from the formation of distal secondary sites called metastases. Several events that lead to cancer are under genetic control. In particular, cancer initiation is tightly associated with specific mutations that affect proto-oncogenes and tumour suppressor genes. These mutations lead to unrestrained growth of the primary neoplasm and a propensity to detach and to progress through the subsequent steps of metastatic dissemination. This process depends tightly on the surrounding microenvironment. In fact, several studies support the point that tumour development relies on a continuous cross-talk between cancer cells and their cellular and extracellular microenvironments. This signaling cross-talk is mediated by transmembrane receptors expressed on cancer cells and stromal cells. The aim of this manuscript is to review how the cancer microenvironment influences the journey of a metastatic cell taking liver invasion by colorectal cancer cells as a model.

No MeSH data available.


Related in: MedlinePlus