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There are several mechanisms by which the aging microenvironment can drive cancer and influence response to therapy, according to a plenary presentation at the AACR virtual meeting II.
Ashani T. Weeraratna, PhD, highlighted research showing how the aging microenvironment affects tumor cell metabolism, angiogenesis, and treatment resistance in melanoma.
Dr. Weeraratna, of Johns Hopkins Bloomberg School of Public Health in Baltimore, first described a study showing how fibroblasts in the aged microenvironment contribute to tumor progression in models of melanoma (Nature. 2016 Apr 14;532[7598]:250-4).
Dr. Weeraratna and colleagues isolated dermal fibroblasts from young human donors (aged 25-35 years) and older donors (55-65 years) and used these cells to produce artificial skin.
Melanoma cells placed in the artificial skin created with young fibroblasts remained “very tightly nested at the surface,” Dr. Weeraratna said. On the other hand, melanoma cells migrated “very rapidly” through the artificial dermis created from aged fibroblasts.
In mouse models of melanoma, tumors grew much faster in young mice (6-8 weeks) than in old mice (12-18 months). However, tumors metastasized to the lung at a “much greater rate in the aged mice than in the young mice,” Dr. Weeraratna said.
Angiogenesis, SFRP2, and VEGF
Dr. Weeraratna went on to explain how a member of her lab conducted proteomic analyses of young and aged lung fibroblasts. The results were compared with results from prior analyses of young and aged skin fibroblasts.
The results showed that aged skin fibroblasts promote noncanonical WNT signaling via expression of SFRP2, SERPINE2, DKK1, Wnt5A, and ROR2. On the other hand, aged lung fibroblasts promote canonical WNT signaling via some of the same family members, including SFRP1, DKK3, and ROR1.
Research by another group showed that SFRP2 stimulates angiogenesis via a calcineurin/NFAT signaling pathway (Cancer Res. 2009 Jun 1;69[11]:4621-8).
Research in Dr. Weeraratna’s lab showed that SFRP2 and VEGF are inversely correlated with aging. Tumors in aged mice had an abundance of SFRP2 but little VEGF. Tumors in young mice had an abundance of VEGF but little SFRP2.
Dr. Weeraratna’s team wanted to determine if results would be similar in melanoma patients, so the researchers analyzed data from the TCGA database. They found that VEGF and two of its key receptors are decreased in older melanoma patients, in comparison with younger melanoma patients.
The clinical relevancy of this finding is reflected in an analysis of data from the AVAST-M study (Ann Oncol. 2019;30[12]:2013-4). When compared with observation, bevacizumab did not improve survival overall or for older patients, but the EGFR inhibitor was associated with longer survival in patients younger than 45 years.
Dr. Weeraratna said this finding and her group’s prior findings suggest younger melanoma patients have more VEGF but less angiogenesis than older patients. The older patients have less VEGF and more SFRP2, which drives angiogenesis.
Dr. Weeraratna’s lab then conducted experiments in young mice, which suggested that an anti-VEGF antibody can reduce angiogenesis, but not in the presence of SFRP2.
Lipid metabolism and treatment resistance
A recently published study by Dr. Weeraratna and colleagues tied changes in aged fibroblast lipid metabolism to treatment resistance in melanoma (Cancer Discov. 2020 Jun 4;CD-20-0329).
The research showed that melanoma cells accumulate lipids when incubated with aged, rather than young, fibroblasts in vitro.
Lipid uptake is mediated by fatty acid transporters (FATPs), and the researchers found that most FATPs were unchanged by age. However, FATP2 was elevated in melanoma cells exposed to aged media, aged mice, and melanoma patients older than 50 years of age.
When melanoma cells were incubated with conditioned media from aged fibroblasts and a FATP2 inhibitor, they no longer took up lipids.
When FATP2 was knocked down in aged mice with melanoma, BRAF and MEK inhibitors (which are not very effective ordinarily) caused dramatic and prolonged tumor regression. These effects were not seen with FATP2 inhibition in young mice.
These results suggest FATP2 is a key transporter of lipids in the aged microenvironment, and inhibiting FATP2 can delay the onset of treatment resistance.
Striving to understand a complex system
For many years, the dogma was that cancer cells behaved like unwelcome invaders, co-opting the metabolic machinery of the sites of spread, with crowding of the normal structures within those organs.
To say that concept was primitive is an understatement. Clearly, the relationship between tumor cells and the surrounding stroma is complex. Changes that occur in an aging microenvironment can influence cancer outcomes in older adults.
Dr. Weeraratna’s presentation adds further impetus to efforts to broaden eligibility criteria for clinical trials so the median age and the metabolic milieu of trial participants more closely parallels the general population.
She highlighted the importance of data analysis by age cohorts and the need to design preclinical studies so that investigators can study the microenvironment of cancer cells in in vitro models and in young and older laboratory animals.
As management expert W. Edwards Deming is believed to have said, “Every system is perfectly designed to get the results it gets.” Cancer is likely not an independent, hostile invader, overtaking the failing machinery of aging cells. To understand the intersection of cancer and aging, we need a more perfect understanding of the system in which tumors develop and are treated.
Dr. Weeraratna reported having no disclosures.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
SOURCE: Weeraratna A. AACR 2020. Age against the machine: How the aging microenvironment governs response to therapy.
There are several mechanisms by which the aging microenvironment can drive cancer and influence response to therapy, according to a plenary presentation at the AACR virtual meeting II.
Ashani T. Weeraratna, PhD, highlighted research showing how the aging microenvironment affects tumor cell metabolism, angiogenesis, and treatment resistance in melanoma.
Dr. Weeraratna, of Johns Hopkins Bloomberg School of Public Health in Baltimore, first described a study showing how fibroblasts in the aged microenvironment contribute to tumor progression in models of melanoma (Nature. 2016 Apr 14;532[7598]:250-4).
Dr. Weeraratna and colleagues isolated dermal fibroblasts from young human donors (aged 25-35 years) and older donors (55-65 years) and used these cells to produce artificial skin.
Melanoma cells placed in the artificial skin created with young fibroblasts remained “very tightly nested at the surface,” Dr. Weeraratna said. On the other hand, melanoma cells migrated “very rapidly” through the artificial dermis created from aged fibroblasts.
In mouse models of melanoma, tumors grew much faster in young mice (6-8 weeks) than in old mice (12-18 months). However, tumors metastasized to the lung at a “much greater rate in the aged mice than in the young mice,” Dr. Weeraratna said.
Angiogenesis, SFRP2, and VEGF
Dr. Weeraratna went on to explain how a member of her lab conducted proteomic analyses of young and aged lung fibroblasts. The results were compared with results from prior analyses of young and aged skin fibroblasts.
The results showed that aged skin fibroblasts promote noncanonical WNT signaling via expression of SFRP2, SERPINE2, DKK1, Wnt5A, and ROR2. On the other hand, aged lung fibroblasts promote canonical WNT signaling via some of the same family members, including SFRP1, DKK3, and ROR1.
Research by another group showed that SFRP2 stimulates angiogenesis via a calcineurin/NFAT signaling pathway (Cancer Res. 2009 Jun 1;69[11]:4621-8).
Research in Dr. Weeraratna’s lab showed that SFRP2 and VEGF are inversely correlated with aging. Tumors in aged mice had an abundance of SFRP2 but little VEGF. Tumors in young mice had an abundance of VEGF but little SFRP2.
Dr. Weeraratna’s team wanted to determine if results would be similar in melanoma patients, so the researchers analyzed data from the TCGA database. They found that VEGF and two of its key receptors are decreased in older melanoma patients, in comparison with younger melanoma patients.
The clinical relevancy of this finding is reflected in an analysis of data from the AVAST-M study (Ann Oncol. 2019;30[12]:2013-4). When compared with observation, bevacizumab did not improve survival overall or for older patients, but the EGFR inhibitor was associated with longer survival in patients younger than 45 years.
Dr. Weeraratna said this finding and her group’s prior findings suggest younger melanoma patients have more VEGF but less angiogenesis than older patients. The older patients have less VEGF and more SFRP2, which drives angiogenesis.
Dr. Weeraratna’s lab then conducted experiments in young mice, which suggested that an anti-VEGF antibody can reduce angiogenesis, but not in the presence of SFRP2.
Lipid metabolism and treatment resistance
A recently published study by Dr. Weeraratna and colleagues tied changes in aged fibroblast lipid metabolism to treatment resistance in melanoma (Cancer Discov. 2020 Jun 4;CD-20-0329).
The research showed that melanoma cells accumulate lipids when incubated with aged, rather than young, fibroblasts in vitro.
Lipid uptake is mediated by fatty acid transporters (FATPs), and the researchers found that most FATPs were unchanged by age. However, FATP2 was elevated in melanoma cells exposed to aged media, aged mice, and melanoma patients older than 50 years of age.
When melanoma cells were incubated with conditioned media from aged fibroblasts and a FATP2 inhibitor, they no longer took up lipids.
When FATP2 was knocked down in aged mice with melanoma, BRAF and MEK inhibitors (which are not very effective ordinarily) caused dramatic and prolonged tumor regression. These effects were not seen with FATP2 inhibition in young mice.
These results suggest FATP2 is a key transporter of lipids in the aged microenvironment, and inhibiting FATP2 can delay the onset of treatment resistance.
Striving to understand a complex system
For many years, the dogma was that cancer cells behaved like unwelcome invaders, co-opting the metabolic machinery of the sites of spread, with crowding of the normal structures within those organs.
To say that concept was primitive is an understatement. Clearly, the relationship between tumor cells and the surrounding stroma is complex. Changes that occur in an aging microenvironment can influence cancer outcomes in older adults.
Dr. Weeraratna’s presentation adds further impetus to efforts to broaden eligibility criteria for clinical trials so the median age and the metabolic milieu of trial participants more closely parallels the general population.
She highlighted the importance of data analysis by age cohorts and the need to design preclinical studies so that investigators can study the microenvironment of cancer cells in in vitro models and in young and older laboratory animals.
As management expert W. Edwards Deming is believed to have said, “Every system is perfectly designed to get the results it gets.” Cancer is likely not an independent, hostile invader, overtaking the failing machinery of aging cells. To understand the intersection of cancer and aging, we need a more perfect understanding of the system in which tumors develop and are treated.
Dr. Weeraratna reported having no disclosures.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
SOURCE: Weeraratna A. AACR 2020. Age against the machine: How the aging microenvironment governs response to therapy.
There are several mechanisms by which the aging microenvironment can drive cancer and influence response to therapy, according to a plenary presentation at the AACR virtual meeting II.
Ashani T. Weeraratna, PhD, highlighted research showing how the aging microenvironment affects tumor cell metabolism, angiogenesis, and treatment resistance in melanoma.
Dr. Weeraratna, of Johns Hopkins Bloomberg School of Public Health in Baltimore, first described a study showing how fibroblasts in the aged microenvironment contribute to tumor progression in models of melanoma (Nature. 2016 Apr 14;532[7598]:250-4).
Dr. Weeraratna and colleagues isolated dermal fibroblasts from young human donors (aged 25-35 years) and older donors (55-65 years) and used these cells to produce artificial skin.
Melanoma cells placed in the artificial skin created with young fibroblasts remained “very tightly nested at the surface,” Dr. Weeraratna said. On the other hand, melanoma cells migrated “very rapidly” through the artificial dermis created from aged fibroblasts.
In mouse models of melanoma, tumors grew much faster in young mice (6-8 weeks) than in old mice (12-18 months). However, tumors metastasized to the lung at a “much greater rate in the aged mice than in the young mice,” Dr. Weeraratna said.
Angiogenesis, SFRP2, and VEGF
Dr. Weeraratna went on to explain how a member of her lab conducted proteomic analyses of young and aged lung fibroblasts. The results were compared with results from prior analyses of young and aged skin fibroblasts.
The results showed that aged skin fibroblasts promote noncanonical WNT signaling via expression of SFRP2, SERPINE2, DKK1, Wnt5A, and ROR2. On the other hand, aged lung fibroblasts promote canonical WNT signaling via some of the same family members, including SFRP1, DKK3, and ROR1.
Research by another group showed that SFRP2 stimulates angiogenesis via a calcineurin/NFAT signaling pathway (Cancer Res. 2009 Jun 1;69[11]:4621-8).
Research in Dr. Weeraratna’s lab showed that SFRP2 and VEGF are inversely correlated with aging. Tumors in aged mice had an abundance of SFRP2 but little VEGF. Tumors in young mice had an abundance of VEGF but little SFRP2.
Dr. Weeraratna’s team wanted to determine if results would be similar in melanoma patients, so the researchers analyzed data from the TCGA database. They found that VEGF and two of its key receptors are decreased in older melanoma patients, in comparison with younger melanoma patients.
The clinical relevancy of this finding is reflected in an analysis of data from the AVAST-M study (Ann Oncol. 2019;30[12]:2013-4). When compared with observation, bevacizumab did not improve survival overall or for older patients, but the EGFR inhibitor was associated with longer survival in patients younger than 45 years.
Dr. Weeraratna said this finding and her group’s prior findings suggest younger melanoma patients have more VEGF but less angiogenesis than older patients. The older patients have less VEGF and more SFRP2, which drives angiogenesis.
Dr. Weeraratna’s lab then conducted experiments in young mice, which suggested that an anti-VEGF antibody can reduce angiogenesis, but not in the presence of SFRP2.
Lipid metabolism and treatment resistance
A recently published study by Dr. Weeraratna and colleagues tied changes in aged fibroblast lipid metabolism to treatment resistance in melanoma (Cancer Discov. 2020 Jun 4;CD-20-0329).
The research showed that melanoma cells accumulate lipids when incubated with aged, rather than young, fibroblasts in vitro.
Lipid uptake is mediated by fatty acid transporters (FATPs), and the researchers found that most FATPs were unchanged by age. However, FATP2 was elevated in melanoma cells exposed to aged media, aged mice, and melanoma patients older than 50 years of age.
When melanoma cells were incubated with conditioned media from aged fibroblasts and a FATP2 inhibitor, they no longer took up lipids.
When FATP2 was knocked down in aged mice with melanoma, BRAF and MEK inhibitors (which are not very effective ordinarily) caused dramatic and prolonged tumor regression. These effects were not seen with FATP2 inhibition in young mice.
These results suggest FATP2 is a key transporter of lipids in the aged microenvironment, and inhibiting FATP2 can delay the onset of treatment resistance.
Striving to understand a complex system
For many years, the dogma was that cancer cells behaved like unwelcome invaders, co-opting the metabolic machinery of the sites of spread, with crowding of the normal structures within those organs.
To say that concept was primitive is an understatement. Clearly, the relationship between tumor cells and the surrounding stroma is complex. Changes that occur in an aging microenvironment can influence cancer outcomes in older adults.
Dr. Weeraratna’s presentation adds further impetus to efforts to broaden eligibility criteria for clinical trials so the median age and the metabolic milieu of trial participants more closely parallels the general population.
She highlighted the importance of data analysis by age cohorts and the need to design preclinical studies so that investigators can study the microenvironment of cancer cells in in vitro models and in young and older laboratory animals.
As management expert W. Edwards Deming is believed to have said, “Every system is perfectly designed to get the results it gets.” Cancer is likely not an independent, hostile invader, overtaking the failing machinery of aging cells. To understand the intersection of cancer and aging, we need a more perfect understanding of the system in which tumors develop and are treated.
Dr. Weeraratna reported having no disclosures.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
SOURCE: Weeraratna A. AACR 2020. Age against the machine: How the aging microenvironment governs response to therapy.
FROM AACR 2020