- Email: [email protected]
Avoiding Overtreatment of Ductal Carcinoma in situ
Trends in Cancer
Forum Therefore, it is of the upmost importance to learn how to distinguish harmless from potentially hazardous DCIS to spare many women needless, but burdensome intensive treatment.
Adjuvant hormonal therapy is not commonly administered for DCIS. Two randomized clinical trials have investigated the role of tamoxifen in DCIS, resulting in a reduction of in situ recurrences, but not Carolien L. van der Borden,1 of invasive recurrences [7,8]. Due to the adverse effects of hormonal therapy and Saskia Stoffers,1 DCIS Risks, Treatment, and 1 ambiguous results of these trials, postEsther H. Lips, and Outcome 1,2,3, menopausal women with DCIS are not * Jelle Wesseling Patients diagnosed with DCIS have an routinely treated by tamoxifen, although increased risk of development of subsequent there are differences between countries. IBC [2]. Low-risk DCIS implies a low risk Ductal carcinoma in situ (DCIS), a of developing subsequent IBC. If low- Currently, three randomized trials are ongoing already, testing the safety of precursor to invasive breast cancer risk DCIS does progress into IBC, this active surveillance for low-risk DCIS as (IBC), represents 25% of all breast will often be a low grade and slowly defined by current clinicopathological neoplasms. Most are harmless, growing tumor with excellent prognosis. criteria (LORIS: NCT02766881ii; COMET: but some progress to IBC. Yet, al- The opposite holds true for high-risk NCT02926911iii; LORD: NCT02492607iv) most all DCIS are treated. Learning DCIS: higher grade, substantially higher (Table 1). how to distinguish harmless from growth rate, and worse prognosis.
Avoiding Overtreatment of Ductal Carcinoma in situ
hazardous DCIS will save many DCIS is treated by BCS often followed DCIS Prognostic Factors women with harmless DCIS the by radiotherapy, or by mastectomy if It is essential to know which factors drive or prevent DCIS progression to invasive disburden of overtreatment. the DCIS lesion is too large to allow breast Ductal carcinoma in situ (DCIS), a potential precursor of invasive breast cancer (IBC), is a proliferation of neoplastic epithelial cells confined to the ductolobular system. To avoid progression to IBC, almost all DCIS are treated by mastectomy or breast-conserving surgery (BCS), with or without subsequent radiotherapy. Survival rates are excellent and similar to women without DCIS. Over 80% of all DCIS lesions are detected by breast cancer screening as implemented about three decades ago. Nowadays, 25% of all breast cancers are DCIS, resulting in over 60 000 new DCIS diagnoses in the USA annually. Yet, the early detection of DCIS has not led to a decline in incidence of advanced stage breast cancer [1], strongly suggesting that screening detects many DCIS lesions that would have never caused symptoms. The resulting overdiagnosis leads to overtreatment. It is still impossible to predict which lesions will progress to IBC and which ones never will. As a consequence, almost all women with DCIS are treated.
conservation. After 10 years median follow-up, invasive recurrence rates are less than 2% after mastectomy, less than 10% after BCS followed by radiotherapy, and approximately 15% after BCS alone [2]. Women with DCIS have an excellent long-term breast cancer-specific survival, that is, around 98% after 10 years of follow-up, and have a normal life expectancy [3]. Four randomized clinical trials have been performed to investigate the role of radiotherapy after BCS for DCIS after complete local excision. In a metaanalysis, these trials showed a 50% reduction in the risk of (both in situ and invasive) local recurrences after radiotherapy [4]. Remarkably, radiotherapy did not affect overall survival rates [4]. A recent study based on analysis of data from the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) databasei on a cohort of more than 100 000 women diagnosed with DCIS suggests that aggressive treatment may not be necessary to save lives, showing the same overall and breast-cancerspecific survival rates without surgery [5,6].
ease. Although a multitude of molecular studies have been performed on this issue, these are often based on small and biased series. Therefore, no robust biomarker is in the clinic yet [9]. Markers associated with DCIS progression include COX2, HER2, p16, and histological grade. A multigene classifier (Oncotype DX Breast Recurrence Scorev) is now being tested in clinical trials to select patient with a high recurrence risk for adjuvant radiotherapy.
DCIS Progression Models The following, not mutually exclusive, even partially complementary evolutionary models have been proposed to describe the progression of DCIS to IBC, that is, an independent lineage model, a convergent phenotype model, an evolutionary bottleneck model, and a multiclonal invasion model (Figure 1). It remains elusive to which extent such models will be integrated in risk stratification assessment and, ultimately, might be helpful in clinical practice.
Future Perspectives Obviously, there is an urgent need to better discriminate indolent from aggressive Trends in Cancer, July 2019, Vol. 5, No. 7
391
Trends in Cancer
Table 1. Three Ongoing Randomized Clinical Trials Testing Safety of Active Surveillance of Low-Risk DCIS LORISii
COMETiii
LORDiv
Country
UK
USA
EU
Age (yr)
≥46
≥40
≥45
Control arm
Standard local care
Standard local care
Standard local care
Study arm
Active surveillance
Active surveillance +/− endocrine therapy (optional)
Active surveillance
Time to primary endpoint (yr)
5
2
10
Study opened
2014/2016
2017
2017
Sites
63
79
28
Patients
113
253
35
Accrual target
932
1200
1240
DCIS. This requires integrated, novel, and comprehensive approaches. The US Patient-Centered Outcomes Research Institutevi prioritizes the evidence gaps in DCIS that need to be addressed to learn
which DCIS are prone to progress to IBC and which ones are not [10]. To do so, the Grand Challenge PRECISION Initiativevii, awarded by Cancer Research UKviii and KWF Dutch Cancer Societyix,
was launched in May 2017. PRECISION, acronym for ‘PREvent ductal Carcinoma In Situ Invasive Overtreatment Now’, takes such an integrative, multidisciplinary approach by analyzing in detail molecular,
Trends in Cancer
Figure 1. Models Describing Progression of DCIS to IDC. (A) Independent lineage model: in situ and invasive cell populations seem to arise from different cell lineages, developing in parallel and independently from each other [11]. (B) Convergent phenotype model: different genotypes of DCIS lead to IBC of the same phenotype, as similarity in genomic profiles was demonstrated between DCIS and adjacent IBC. However, some DCIS cases and its adjacent IBC differ in copy number and gene mutations, suggesting that progression might be driven by specific clones [12]. (C) Evolutionary bottleneck model: individual DCIS cells accumulate different genetic properties. Only a subpopulation of these with a specific genetic profile overcome an evolutionary bottleneck enabling invasion into the adjacent tissue [13]. (D) Multiclonal invasion model: multiple clones escape from the ducts and comigrate into the adjacent tissue to establish invasive carcinomas [11]. Abbreviations: DCIS = ductal carcinoma in situ; IBC = invasive breast cancer. (Adapted from: doi 10.1038/s41416-019-0478-6)
392
Trends in Cancer, July 2019, Vol. 5, No. 7
Trends in Cancer
microenvironmental, and imaging features of large series of DCIS with long-term follow-up to assess which factors are associated with either harmless or potentially hazardous DCIS, and how these relate to the underlying mechanisms of whether progression might occur or not. Results obtained will be integrated to develop a DCIS risk prediction model. The findings will be prospectively validated in three randomized clinical trials (LORIS, COMET, and LORD) testing the safety of active surveillance for low-risk DCIS. To conquer overtreatment of DCIS, the role of patients cannot be underestimated. They help healthcare providers to focus on the ultimate question distinguishing harmless from potentially hazardous DCIS. This has to be related to their quality of life, including how they cope with uncertainties regarding the risks involved. The comprehensive approach as described above eventually aims to spare many thousands of women needless, but burdensome treatment each year, without compromising the excellent outcomes presently achieved in the management of DCIS. Resources i
https://seer.cancer.gov/
ii
https://clinicaltrials.gov/ct2/show/NCT02766881
iii
https://clinicaltrials.gov/ct2/show/NCT02926911
iv
https://clinicaltrials.gov/ct2/show/NCT02492607
v
https://www.oncotypeiq.com/en-US/breast-cancer/
healthcare-professionals/oncotype-dx-breastrecurrence-score/about-the-test vi
https://www.pcori.org/
vii
https://www.dcisprecision.org/
viii
https://www.cancerresearchuk.org/
ix
https://www.kwf.nl/english/pages/default.aspx
1 Division of Molecular Pathology, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands 2 Division of Diagnostic Oncology, Department of Pathology, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands 3 Department of Pathology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands
*Correspondence: [email protected] (J. Wesseling). https://doi.org/10.1016/j.trecan.2019.05.005
© 2019 Elsevier Inc. All rights reserved.
References 1. Autier, P. et al. (2017) Effectiveness of and overdiagnosis from mammography screening in the Netherlands: population based study. BMJ 359, j5224–j5229 2. Elshof, L.E. et al. (2016) Subsequent risk of ipsilateral and contralateral invasive breast cancer after treatment for ductal carcinoma in situ: incidence and the effect of radiotherapy in a population-based cohort of 10,090 women. Breast Cancer Res. Treat. 159, 553–563 3. Elshof, L.E. et al. (2018) Cause-specific mortality in a population-based cohort of 9799 women treated for ductal carcinoma in situ. Ann. Surg. 267, 952–958 4. Early Breast Cancer Trialists’ Collaborative Group et al. (2010) Overview of the randomized trials of radiotherapy in ductal carcinoma in situ of the breast. J. Natl. Cancer Inst. Monogr. 2010, 162–177 5. Narod, S.A. et al. (2015) Breast cancer mortality after a diagnosis of ductal carcinoma in situ. JAMA Oncol. 1, 888–896 6. Worni, M. et al. (2015) Trends in treatment patterns and outcomes for ductal carcinoma in situ. J. Natl. Cancer Inst. 107, djv263 7. Cuzick, J. et al. (2011) Effect of tamoxifen and radiotherapy in women with locally excised ductal carcinoma in situ: long-term results from the UK/ANZ DCIS trial. Lancet Oncol 12, 21–29 8. Wapnir, I.L. et al. (2011) Long-term outcomes of invasive ipsilateral breast tumor recurrences after lumpectomy in NSABP B-17 and B-24 randomized clinical trials for DCIS. J. Natl. Cancer Inst. 103, 478–488 9. Visser, L.L. et al. (2019) Predictors of an invasive breast cancer recurrence after DCIS: a systematic review and meta-analyses. Cancer Epidemiol. Biomarkers Prev. 28, 835–845 10. Gierisch, J.M. et al. (2014) Prioritization of research addressing management strategies for ductal carcinoma in situ. Ann. Intern. Med. 160, 484–491 11. Casasent, A.K. et al. (2018) Multiclonal invasion in breast tumors identified by topographic single cell sequencing. Cell 172, 205–217 12. Hernandez, L. et al. (2012) Genomic and mutational profiling of ductal carcinomas in situ and matched adjacent invasive breast cancers reveals intra-tumour genetic heterogeneity and clonal selection. J. Pathol. 227, 42–52 13. Kim, S.Y. et al. (2015) Genomic differences between pure ductal carcinoma in situ and synchronous ductal carcinoma in situ with invasive breast cancer. Oncotarget 6, 7597–7607
exosomes, to transfer immune modulating molecules to immune cells, resulting in an immune privileged microenvironment. Here we discuss the potential EV-mediated mechanisms underlying glioma immune modulation, as well as the technical difficulties in studying these interactions.
Glioblastomas are the most common and lethal intracranial primary malignancies in adults. They are heterogeneous tumors with tumor cells and nonmalignant stromal cells [1]. The stromal population consists of resident brain glial cells, including oligodendrocytes, astrocytes, ependymal cells, and microglia; and infiltrating immune cells, such as myeloid-derived monocytes/macrophages and lymphocytes [1]. Together, the stromal and malignant cells form a microenvironment that in general enables the tumor cells to proliferate and infiltrate [1]. Within this microenvironment, cells communicate through secretion of cytokines and other (soluble) proteins, direct cell–cell contact through gap junctions or nanotubes, and extracellular vesicles (EVs) [1]. EVs is the collective term for nanosized and microsized (~50– 10 000 nm) membrane-enclosed vesicles that are released by all cell types [2]. As different cellular pathways can result in Forum the release of EVs, different terminology (e.g., exosomes, microvesicles, ectosomes) has been used for the potential subpopulations of EVs (Figure 1) [2,3]. However, since clear markers for these subpopulations are lacking, current consensus is to use the 1,2 umbrella term ‘EVs’ [3]. EVs have a similar Erik R. Abels, 1,2,3,4 membrane topology as their cells of origin, Marike L.D. Broekman, 1,2 and thus (mutant) extracellular domains of Xandra O. Breakefield, and transmembrane proteins can be present 5,6, Sybren L.N. Maas * on the surface of EVs. Simultaneously, donor cell cytosolic components, such as (mutant) proteins, m(i)RNA, and DNA Glioblastoma cells release extra- molecules, are contained as cargo inside cellular vesicles (EVs), sometimes EVs and can be transferred from donor to referred to as microvesicles and recipient cells. This transfer of receptor
Glioma EVs Contribute to Immune Privilege in the Brain
Trends in Cancer, July 2019, Vol. 5, No. 7
393
Forum Therefore, it is of the upmost importance to learn how to distinguish harmless from potentially hazardous DCIS to spare many women needless, but burdensome intensive treatment.
Adjuvant hormonal therapy is not commonly administered for DCIS. Two randomized clinical trials have investigated the role of tamoxifen in DCIS, resulting in a reduction of in situ recurrences, but not Carolien L. van der Borden,1 of invasive recurrences [7,8]. Due to the adverse effects of hormonal therapy and Saskia Stoffers,1 DCIS Risks, Treatment, and 1 ambiguous results of these trials, postEsther H. Lips, and Outcome 1,2,3, menopausal women with DCIS are not * Jelle Wesseling Patients diagnosed with DCIS have an routinely treated by tamoxifen, although increased risk of development of subsequent there are differences between countries. IBC [2]. Low-risk DCIS implies a low risk Ductal carcinoma in situ (DCIS), a of developing subsequent IBC. If low- Currently, three randomized trials are ongoing already, testing the safety of precursor to invasive breast cancer risk DCIS does progress into IBC, this active surveillance for low-risk DCIS as (IBC), represents 25% of all breast will often be a low grade and slowly defined by current clinicopathological neoplasms. Most are harmless, growing tumor with excellent prognosis. criteria (LORIS: NCT02766881ii; COMET: but some progress to IBC. Yet, al- The opposite holds true for high-risk NCT02926911iii; LORD: NCT02492607iv) most all DCIS are treated. Learning DCIS: higher grade, substantially higher (Table 1). how to distinguish harmless from growth rate, and worse prognosis.
Avoiding Overtreatment of Ductal Carcinoma in situ
hazardous DCIS will save many DCIS is treated by BCS often followed DCIS Prognostic Factors women with harmless DCIS the by radiotherapy, or by mastectomy if It is essential to know which factors drive or prevent DCIS progression to invasive disburden of overtreatment. the DCIS lesion is too large to allow breast Ductal carcinoma in situ (DCIS), a potential precursor of invasive breast cancer (IBC), is a proliferation of neoplastic epithelial cells confined to the ductolobular system. To avoid progression to IBC, almost all DCIS are treated by mastectomy or breast-conserving surgery (BCS), with or without subsequent radiotherapy. Survival rates are excellent and similar to women without DCIS. Over 80% of all DCIS lesions are detected by breast cancer screening as implemented about three decades ago. Nowadays, 25% of all breast cancers are DCIS, resulting in over 60 000 new DCIS diagnoses in the USA annually. Yet, the early detection of DCIS has not led to a decline in incidence of advanced stage breast cancer [1], strongly suggesting that screening detects many DCIS lesions that would have never caused symptoms. The resulting overdiagnosis leads to overtreatment. It is still impossible to predict which lesions will progress to IBC and which ones never will. As a consequence, almost all women with DCIS are treated.
conservation. After 10 years median follow-up, invasive recurrence rates are less than 2% after mastectomy, less than 10% after BCS followed by radiotherapy, and approximately 15% after BCS alone [2]. Women with DCIS have an excellent long-term breast cancer-specific survival, that is, around 98% after 10 years of follow-up, and have a normal life expectancy [3]. Four randomized clinical trials have been performed to investigate the role of radiotherapy after BCS for DCIS after complete local excision. In a metaanalysis, these trials showed a 50% reduction in the risk of (both in situ and invasive) local recurrences after radiotherapy [4]. Remarkably, radiotherapy did not affect overall survival rates [4]. A recent study based on analysis of data from the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) databasei on a cohort of more than 100 000 women diagnosed with DCIS suggests that aggressive treatment may not be necessary to save lives, showing the same overall and breast-cancerspecific survival rates without surgery [5,6].
ease. Although a multitude of molecular studies have been performed on this issue, these are often based on small and biased series. Therefore, no robust biomarker is in the clinic yet [9]. Markers associated with DCIS progression include COX2, HER2, p16, and histological grade. A multigene classifier (Oncotype DX Breast Recurrence Scorev) is now being tested in clinical trials to select patient with a high recurrence risk for adjuvant radiotherapy.
DCIS Progression Models The following, not mutually exclusive, even partially complementary evolutionary models have been proposed to describe the progression of DCIS to IBC, that is, an independent lineage model, a convergent phenotype model, an evolutionary bottleneck model, and a multiclonal invasion model (Figure 1). It remains elusive to which extent such models will be integrated in risk stratification assessment and, ultimately, might be helpful in clinical practice.
Future Perspectives Obviously, there is an urgent need to better discriminate indolent from aggressive Trends in Cancer, July 2019, Vol. 5, No. 7
391
Trends in Cancer
Table 1. Three Ongoing Randomized Clinical Trials Testing Safety of Active Surveillance of Low-Risk DCIS LORISii
COMETiii
LORDiv
Country
UK
USA
EU
Age (yr)
≥46
≥40
≥45
Control arm
Standard local care
Standard local care
Standard local care
Study arm
Active surveillance
Active surveillance +/− endocrine therapy (optional)
Active surveillance
Time to primary endpoint (yr)
5
2
10
Study opened
2014/2016
2017
2017
Sites
63
79
28
Patients
113
253
35
Accrual target
932
1200
1240
DCIS. This requires integrated, novel, and comprehensive approaches. The US Patient-Centered Outcomes Research Institutevi prioritizes the evidence gaps in DCIS that need to be addressed to learn
which DCIS are prone to progress to IBC and which ones are not [10]. To do so, the Grand Challenge PRECISION Initiativevii, awarded by Cancer Research UKviii and KWF Dutch Cancer Societyix,
was launched in May 2017. PRECISION, acronym for ‘PREvent ductal Carcinoma In Situ Invasive Overtreatment Now’, takes such an integrative, multidisciplinary approach by analyzing in detail molecular,
Trends in Cancer
Figure 1. Models Describing Progression of DCIS to IDC. (A) Independent lineage model: in situ and invasive cell populations seem to arise from different cell lineages, developing in parallel and independently from each other [11]. (B) Convergent phenotype model: different genotypes of DCIS lead to IBC of the same phenotype, as similarity in genomic profiles was demonstrated between DCIS and adjacent IBC. However, some DCIS cases and its adjacent IBC differ in copy number and gene mutations, suggesting that progression might be driven by specific clones [12]. (C) Evolutionary bottleneck model: individual DCIS cells accumulate different genetic properties. Only a subpopulation of these with a specific genetic profile overcome an evolutionary bottleneck enabling invasion into the adjacent tissue [13]. (D) Multiclonal invasion model: multiple clones escape from the ducts and comigrate into the adjacent tissue to establish invasive carcinomas [11]. Abbreviations: DCIS = ductal carcinoma in situ; IBC = invasive breast cancer. (Adapted from: doi 10.1038/s41416-019-0478-6)
392
Trends in Cancer, July 2019, Vol. 5, No. 7
Trends in Cancer
microenvironmental, and imaging features of large series of DCIS with long-term follow-up to assess which factors are associated with either harmless or potentially hazardous DCIS, and how these relate to the underlying mechanisms of whether progression might occur or not. Results obtained will be integrated to develop a DCIS risk prediction model. The findings will be prospectively validated in three randomized clinical trials (LORIS, COMET, and LORD) testing the safety of active surveillance for low-risk DCIS. To conquer overtreatment of DCIS, the role of patients cannot be underestimated. They help healthcare providers to focus on the ultimate question distinguishing harmless from potentially hazardous DCIS. This has to be related to their quality of life, including how they cope with uncertainties regarding the risks involved. The comprehensive approach as described above eventually aims to spare many thousands of women needless, but burdensome treatment each year, without compromising the excellent outcomes presently achieved in the management of DCIS. Resources i
https://seer.cancer.gov/
ii
https://clinicaltrials.gov/ct2/show/NCT02766881
iii
https://clinicaltrials.gov/ct2/show/NCT02926911
iv
https://clinicaltrials.gov/ct2/show/NCT02492607
v
https://www.oncotypeiq.com/en-US/breast-cancer/
healthcare-professionals/oncotype-dx-breastrecurrence-score/about-the-test vi
https://www.pcori.org/
vii
https://www.dcisprecision.org/
viii
https://www.cancerresearchuk.org/
ix
https://www.kwf.nl/english/pages/default.aspx
1 Division of Molecular Pathology, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands 2 Division of Diagnostic Oncology, Department of Pathology, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands 3 Department of Pathology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands
*Correspondence: [email protected] (J. Wesseling). https://doi.org/10.1016/j.trecan.2019.05.005
© 2019 Elsevier Inc. All rights reserved.
References 1. Autier, P. et al. (2017) Effectiveness of and overdiagnosis from mammography screening in the Netherlands: population based study. BMJ 359, j5224–j5229 2. Elshof, L.E. et al. (2016) Subsequent risk of ipsilateral and contralateral invasive breast cancer after treatment for ductal carcinoma in situ: incidence and the effect of radiotherapy in a population-based cohort of 10,090 women. Breast Cancer Res. Treat. 159, 553–563 3. Elshof, L.E. et al. (2018) Cause-specific mortality in a population-based cohort of 9799 women treated for ductal carcinoma in situ. Ann. Surg. 267, 952–958 4. Early Breast Cancer Trialists’ Collaborative Group et al. (2010) Overview of the randomized trials of radiotherapy in ductal carcinoma in situ of the breast. J. Natl. Cancer Inst. Monogr. 2010, 162–177 5. Narod, S.A. et al. (2015) Breast cancer mortality after a diagnosis of ductal carcinoma in situ. JAMA Oncol. 1, 888–896 6. Worni, M. et al. (2015) Trends in treatment patterns and outcomes for ductal carcinoma in situ. J. Natl. Cancer Inst. 107, djv263 7. Cuzick, J. et al. (2011) Effect of tamoxifen and radiotherapy in women with locally excised ductal carcinoma in situ: long-term results from the UK/ANZ DCIS trial. Lancet Oncol 12, 21–29 8. Wapnir, I.L. et al. (2011) Long-term outcomes of invasive ipsilateral breast tumor recurrences after lumpectomy in NSABP B-17 and B-24 randomized clinical trials for DCIS. J. Natl. Cancer Inst. 103, 478–488 9. Visser, L.L. et al. (2019) Predictors of an invasive breast cancer recurrence after DCIS: a systematic review and meta-analyses. Cancer Epidemiol. Biomarkers Prev. 28, 835–845 10. Gierisch, J.M. et al. (2014) Prioritization of research addressing management strategies for ductal carcinoma in situ. Ann. Intern. Med. 160, 484–491 11. Casasent, A.K. et al. (2018) Multiclonal invasion in breast tumors identified by topographic single cell sequencing. Cell 172, 205–217 12. Hernandez, L. et al. (2012) Genomic and mutational profiling of ductal carcinomas in situ and matched adjacent invasive breast cancers reveals intra-tumour genetic heterogeneity and clonal selection. J. Pathol. 227, 42–52 13. Kim, S.Y. et al. (2015) Genomic differences between pure ductal carcinoma in situ and synchronous ductal carcinoma in situ with invasive breast cancer. Oncotarget 6, 7597–7607
exosomes, to transfer immune modulating molecules to immune cells, resulting in an immune privileged microenvironment. Here we discuss the potential EV-mediated mechanisms underlying glioma immune modulation, as well as the technical difficulties in studying these interactions.
Glioblastomas are the most common and lethal intracranial primary malignancies in adults. They are heterogeneous tumors with tumor cells and nonmalignant stromal cells [1]. The stromal population consists of resident brain glial cells, including oligodendrocytes, astrocytes, ependymal cells, and microglia; and infiltrating immune cells, such as myeloid-derived monocytes/macrophages and lymphocytes [1]. Together, the stromal and malignant cells form a microenvironment that in general enables the tumor cells to proliferate and infiltrate [1]. Within this microenvironment, cells communicate through secretion of cytokines and other (soluble) proteins, direct cell–cell contact through gap junctions or nanotubes, and extracellular vesicles (EVs) [1]. EVs is the collective term for nanosized and microsized (~50– 10 000 nm) membrane-enclosed vesicles that are released by all cell types [2]. As different cellular pathways can result in Forum the release of EVs, different terminology (e.g., exosomes, microvesicles, ectosomes) has been used for the potential subpopulations of EVs (Figure 1) [2,3]. However, since clear markers for these subpopulations are lacking, current consensus is to use the 1,2 umbrella term ‘EVs’ [3]. EVs have a similar Erik R. Abels, 1,2,3,4 membrane topology as their cells of origin, Marike L.D. Broekman, 1,2 and thus (mutant) extracellular domains of Xandra O. Breakefield, and transmembrane proteins can be present 5,6, Sybren L.N. Maas * on the surface of EVs. Simultaneously, donor cell cytosolic components, such as (mutant) proteins, m(i)RNA, and DNA Glioblastoma cells release extra- molecules, are contained as cargo inside cellular vesicles (EVs), sometimes EVs and can be transferred from donor to referred to as microvesicles and recipient cells. This transfer of receptor
Glioma EVs Contribute to Immune Privilege in the Brain
Trends in Cancer, July 2019, Vol. 5, No. 7
393