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Brain neoplasms and coagulation-lessons from heterogeneity.

D'Asti E, Fang Y, Rak J - Rambam Maimonides Med J (2014)

Bottom Line: While brain tumor cells express tissue factor (TF) and other effectors of the coagulation system (coagulome), their propensity to induce local and peripheral thrombosis is highly diverse, most dramatic in the case of glioblastoma multiforme (GBM), and less obvious in pediatric tumors.While the immediate medical needs often frame the discussion on current clinical challenges, the coagulation pathway may contribute to brain tumor progression through subtle, context-dependent, and non-coagulant effects, such as induction of inflammation, angiogenesis, or by responding to iatrogenic insults (e.g. surgery).Indeed, oncogenes (EGFR, MET) and tumor suppressors (PTEN, TP53) may alter the expression, activity, and vesicular release of tissue factor (TF), and cause other changes.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, McGill University. Montreal Children's Hospital, The Research Institute of the McGill University Health Centre, Montreal, QC, Canada.

ABSTRACT
The coagulation system constitutes an important facet of the unique vascular microenvironment in which primary and metastatic brain tumors evolve and progress. While brain tumor cells express tissue factor (TF) and other effectors of the coagulation system (coagulome), their propensity to induce local and peripheral thrombosis is highly diverse, most dramatic in the case of glioblastoma multiforme (GBM), and less obvious in pediatric tumors. While the immediate medical needs often frame the discussion on current clinical challenges, the coagulation pathway may contribute to brain tumor progression through subtle, context-dependent, and non-coagulant effects, such as induction of inflammation, angiogenesis, or by responding to iatrogenic insults (e.g. surgery). In this regard, the emerging molecular diversity of brain tumor suptypes (e.g. in glioma and medulloblastoma) highlights the link between oncogenic pathways and the tumor repertoire of coagulation system regulators (coagulome). This relationship may influence the mechanisms of spontaneous and therapeutically provoked tumor cell interactions with the coagulation system as a whole. Indeed, oncogenes (EGFR, MET) and tumor suppressors (PTEN, TP53) may alter the expression, activity, and vesicular release of tissue factor (TF), and cause other changes. Conversely, the coagulant microenvironment may also influence the molecular evolution of brain tumor cells through selective and instructive cues. We suggest that effective targeting of the coagulation system in brain tumors should be explored through molecular stratification, stage-specific analysis, and more personalized approaches including thromboprophylaxis and adjuvant treatment aimed at improvement of patient survival.

No MeSH data available.


Related in: MedlinePlus

Heterogeneity of Brain Tumors as a Possible Source of the Heterogeneous Nature of the Related Coagulopathies.Brain is normally shielded from the coagulation system effectors by the blood–brain barrier (BBB), especially through the properties of the vascular wall. This barrier can be disrupted by injury or chronic pathology, such as cancer, and anti-cancer therapies (e.g. surgery), resulting in contact between brain parenchyma and coagulation factors in blood plasma. We postulate that these interactions could be more heterogeneous than currently thought and may lead to different mechanisms and consequences of coagulation system activation in specific pathological settings. Thus, cancers originate in different regions of the brain, where cells may possess different (currently unstudied) abilities to activate or respond to coagulation factors. Moreover, different brain tumors emerging in such distinct locations may differ in their abilities to activate coagulation. For example, such effects are pronounced and systemic in glioblastoma (GBM), but more subtle and mostly clinically unremarkable in medulloblastoma (MB). In addition, within specific tumor types, such as GBM, recent studies distinguished several molecular subtypes, such as proneural (PN), neural (NEU), classical (CL), and mesenchymal (MES) disease (symbols as indicated). Recent studies revealed that each of these subtypes expresses different repertoires of coagulation effector genes (coagulome).47 Similar diversity in coagulome has also been documented among subtypes of MB, such as wingless (WNT), sonic hedgehog (SHH), group 3 (G3) and group 4 (G4) tumors each driven by different oncogenic pathways. In MB more subtle interactions with the coagulation system may lead to subclinical effects. Finally, each tumor (especially GBM) may contain microregions and diverse cellular subpopulations that may have different coagulant properties. We propose that these factors may need to be considered when exploring the role of the coagulation system in brain tumor biology and the associated coagulopathy (see text).
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f1-rmmj-5-4-e0030: Heterogeneity of Brain Tumors as a Possible Source of the Heterogeneous Nature of the Related Coagulopathies.Brain is normally shielded from the coagulation system effectors by the blood–brain barrier (BBB), especially through the properties of the vascular wall. This barrier can be disrupted by injury or chronic pathology, such as cancer, and anti-cancer therapies (e.g. surgery), resulting in contact between brain parenchyma and coagulation factors in blood plasma. We postulate that these interactions could be more heterogeneous than currently thought and may lead to different mechanisms and consequences of coagulation system activation in specific pathological settings. Thus, cancers originate in different regions of the brain, where cells may possess different (currently unstudied) abilities to activate or respond to coagulation factors. Moreover, different brain tumors emerging in such distinct locations may differ in their abilities to activate coagulation. For example, such effects are pronounced and systemic in glioblastoma (GBM), but more subtle and mostly clinically unremarkable in medulloblastoma (MB). In addition, within specific tumor types, such as GBM, recent studies distinguished several molecular subtypes, such as proneural (PN), neural (NEU), classical (CL), and mesenchymal (MES) disease (symbols as indicated). Recent studies revealed that each of these subtypes expresses different repertoires of coagulation effector genes (coagulome).47 Similar diversity in coagulome has also been documented among subtypes of MB, such as wingless (WNT), sonic hedgehog (SHH), group 3 (G3) and group 4 (G4) tumors each driven by different oncogenic pathways. In MB more subtle interactions with the coagulation system may lead to subclinical effects. Finally, each tumor (especially GBM) may contain microregions and diverse cellular subpopulations that may have different coagulant properties. We propose that these factors may need to be considered when exploring the role of the coagulation system in brain tumor biology and the associated coagulopathy (see text).

Mentions: Thus the vast majority of adult human cancers arise as a result of the accumulation of multiple genetic hits. As the “founder mutation” is compounded by additional mutational events, multiple cellular lineages with different genetic profiles emerge within a single lesion often colonizing different tumor microregions, or coexisting in dynamic mixtures composed of cells with different degrees of aggressiveness.59 Tumors emerging within the same organ site may possess similar histology but differ markedly from each other in terms of their mutational repertoires, such that they could be classified into distinct molecular subtypes of what once may have been thought to be a single diagnostic entity (e.g. GBM). Multiple human tumors exhibit such molecular heterogeneities, including breast, colon, and brain tumors.73–75 Notably, stromal and vascular properties of certain cancers may also serve to distinguish disease subtypes and pathological trajectories,76 a property that could impact coagulopathy, but has not been studied or discussed in this context (Figure 1).


Brain neoplasms and coagulation-lessons from heterogeneity.

D'Asti E, Fang Y, Rak J - Rambam Maimonides Med J (2014)

Heterogeneity of Brain Tumors as a Possible Source of the Heterogeneous Nature of the Related Coagulopathies.Brain is normally shielded from the coagulation system effectors by the blood–brain barrier (BBB), especially through the properties of the vascular wall. This barrier can be disrupted by injury or chronic pathology, such as cancer, and anti-cancer therapies (e.g. surgery), resulting in contact between brain parenchyma and coagulation factors in blood plasma. We postulate that these interactions could be more heterogeneous than currently thought and may lead to different mechanisms and consequences of coagulation system activation in specific pathological settings. Thus, cancers originate in different regions of the brain, where cells may possess different (currently unstudied) abilities to activate or respond to coagulation factors. Moreover, different brain tumors emerging in such distinct locations may differ in their abilities to activate coagulation. For example, such effects are pronounced and systemic in glioblastoma (GBM), but more subtle and mostly clinically unremarkable in medulloblastoma (MB). In addition, within specific tumor types, such as GBM, recent studies distinguished several molecular subtypes, such as proneural (PN), neural (NEU), classical (CL), and mesenchymal (MES) disease (symbols as indicated). Recent studies revealed that each of these subtypes expresses different repertoires of coagulation effector genes (coagulome).47 Similar diversity in coagulome has also been documented among subtypes of MB, such as wingless (WNT), sonic hedgehog (SHH), group 3 (G3) and group 4 (G4) tumors each driven by different oncogenic pathways. In MB more subtle interactions with the coagulation system may lead to subclinical effects. Finally, each tumor (especially GBM) may contain microregions and diverse cellular subpopulations that may have different coagulant properties. We propose that these factors may need to be considered when exploring the role of the coagulation system in brain tumor biology and the associated coagulopathy (see text).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4222419&req=5

f1-rmmj-5-4-e0030: Heterogeneity of Brain Tumors as a Possible Source of the Heterogeneous Nature of the Related Coagulopathies.Brain is normally shielded from the coagulation system effectors by the blood–brain barrier (BBB), especially through the properties of the vascular wall. This barrier can be disrupted by injury or chronic pathology, such as cancer, and anti-cancer therapies (e.g. surgery), resulting in contact between brain parenchyma and coagulation factors in blood plasma. We postulate that these interactions could be more heterogeneous than currently thought and may lead to different mechanisms and consequences of coagulation system activation in specific pathological settings. Thus, cancers originate in different regions of the brain, where cells may possess different (currently unstudied) abilities to activate or respond to coagulation factors. Moreover, different brain tumors emerging in such distinct locations may differ in their abilities to activate coagulation. For example, such effects are pronounced and systemic in glioblastoma (GBM), but more subtle and mostly clinically unremarkable in medulloblastoma (MB). In addition, within specific tumor types, such as GBM, recent studies distinguished several molecular subtypes, such as proneural (PN), neural (NEU), classical (CL), and mesenchymal (MES) disease (symbols as indicated). Recent studies revealed that each of these subtypes expresses different repertoires of coagulation effector genes (coagulome).47 Similar diversity in coagulome has also been documented among subtypes of MB, such as wingless (WNT), sonic hedgehog (SHH), group 3 (G3) and group 4 (G4) tumors each driven by different oncogenic pathways. In MB more subtle interactions with the coagulation system may lead to subclinical effects. Finally, each tumor (especially GBM) may contain microregions and diverse cellular subpopulations that may have different coagulant properties. We propose that these factors may need to be considered when exploring the role of the coagulation system in brain tumor biology and the associated coagulopathy (see text).
Mentions: Thus the vast majority of adult human cancers arise as a result of the accumulation of multiple genetic hits. As the “founder mutation” is compounded by additional mutational events, multiple cellular lineages with different genetic profiles emerge within a single lesion often colonizing different tumor microregions, or coexisting in dynamic mixtures composed of cells with different degrees of aggressiveness.59 Tumors emerging within the same organ site may possess similar histology but differ markedly from each other in terms of their mutational repertoires, such that they could be classified into distinct molecular subtypes of what once may have been thought to be a single diagnostic entity (e.g. GBM). Multiple human tumors exhibit such molecular heterogeneities, including breast, colon, and brain tumors.73–75 Notably, stromal and vascular properties of certain cancers may also serve to distinguish disease subtypes and pathological trajectories,76 a property that could impact coagulopathy, but has not been studied or discussed in this context (Figure 1).

Bottom Line: While brain tumor cells express tissue factor (TF) and other effectors of the coagulation system (coagulome), their propensity to induce local and peripheral thrombosis is highly diverse, most dramatic in the case of glioblastoma multiforme (GBM), and less obvious in pediatric tumors.While the immediate medical needs often frame the discussion on current clinical challenges, the coagulation pathway may contribute to brain tumor progression through subtle, context-dependent, and non-coagulant effects, such as induction of inflammation, angiogenesis, or by responding to iatrogenic insults (e.g. surgery).Indeed, oncogenes (EGFR, MET) and tumor suppressors (PTEN, TP53) may alter the expression, activity, and vesicular release of tissue factor (TF), and cause other changes.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, McGill University. Montreal Children's Hospital, The Research Institute of the McGill University Health Centre, Montreal, QC, Canada.

ABSTRACT
The coagulation system constitutes an important facet of the unique vascular microenvironment in which primary and metastatic brain tumors evolve and progress. While brain tumor cells express tissue factor (TF) and other effectors of the coagulation system (coagulome), their propensity to induce local and peripheral thrombosis is highly diverse, most dramatic in the case of glioblastoma multiforme (GBM), and less obvious in pediatric tumors. While the immediate medical needs often frame the discussion on current clinical challenges, the coagulation pathway may contribute to brain tumor progression through subtle, context-dependent, and non-coagulant effects, such as induction of inflammation, angiogenesis, or by responding to iatrogenic insults (e.g. surgery). In this regard, the emerging molecular diversity of brain tumor suptypes (e.g. in glioma and medulloblastoma) highlights the link between oncogenic pathways and the tumor repertoire of coagulation system regulators (coagulome). This relationship may influence the mechanisms of spontaneous and therapeutically provoked tumor cell interactions with the coagulation system as a whole. Indeed, oncogenes (EGFR, MET) and tumor suppressors (PTEN, TP53) may alter the expression, activity, and vesicular release of tissue factor (TF), and cause other changes. Conversely, the coagulant microenvironment may also influence the molecular evolution of brain tumor cells through selective and instructive cues. We suggest that effective targeting of the coagulation system in brain tumors should be explored through molecular stratification, stage-specific analysis, and more personalized approaches including thromboprophylaxis and adjuvant treatment aimed at improvement of patient survival.

No MeSH data available.


Related in: MedlinePlus