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Contribution of Adipose Tissue to Development of Cancer

Alyssa J. Cozzo, Ashley M. Fuller, Liza Makowski

10.1002/cphy.c170008

Source: Volume 8, Issue 1, January 2018

Published online: December 2017

Full Article on Wiley Online Library



ABSTRACT

Solid tumor growth and metastasis require the interaction of tumor cells with the surrounding tissue, leading to a view of tumors as tissue‐level phenomena rather than exclusively cell‐intrinsic anomalies. Due to the ubiquitous nature of adipose tissue, many types of solid tumors grow in proximate or direct contact with adipocytes and adipose‐associated stromal and vascular components, such as fibroblasts and other connective tissue cells, stem and progenitor cells, endothelial cells, innate and adaptive immune cells, and extracellular signaling and matrix components. Excess adiposity in obesity both increases risk of cancer development and negatively influences prognosis in several cancer types, in part due to interaction with adipose tissue cell populations. Herein, we review the cellular and noncellular constituents of the adipose “organ,” and discuss the mechanisms by which these varied microenvironmental components contribute to tumor development, with special emphasis on obesity. Due to the prevalence of breast and prostate cancers in the United States, their close anatomical proximity to adipose tissue depots, and their complex epidemiologic associations with obesity, we particularly highlight research addressing the contribution of adipose tissue to the initiation and progression of these cancer types. Obesity dramatically modifies the adipose tissue microenvironment in numerous ways, including induction of fibrosis and angiogenesis, increased stem cell abundance, and expansion of proinflammatory immune cells. As many of these changes also resemble shifts observed within the tumor microenvironment, proximity to adipose tissue may present a hospitable environment to developing tumors, providing a critical link between adiposity and tumorigenesis. © 2018 American Physiological Society. Compr Physiol 8:237‐282, 2018.

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Figure 1. Figure 1. Tumors as communities. Tumor cells coexist with a variety of stromal and immune cells, and reside in a complex mixture of signaling molecules and extracellular matrix components. Adjacent adipose tissue may provide a hospitable environment to developing tumors.
Figure 2. Figure 2. The adipose organ is comprised of several distinct adipose depots. Adipose depot locations and subtypes in (A) humans and (B) mice [panel B adapted from (85) with permission].
Figure 3. Figure 3. Approximate composition of human white adipose tissue stromal‐vascular fraction (percent cellularity).
Figure 4. Figure 4. Rising global and US obesity rates. (A) Global age‐adjusted prevalence of obesity in men and women, 1975 and 2014; (B) Class III obesity (BMI >40), globally and US; and (C) US obesity prevalence by race, ethnicity (270).
Figure 5. Figure 5. Comparison of mouse and human mammary gland anatomical structure. (A) Murine ductal elongation and branching occur at the Terminal End Buds (TEBs). (B) The human mammary gland is extensively branched, culminating in the functional terminal ductal lobular unit (TDLU).
Figure 6. Figure 6. Comparison of mouse and human mammary gland histology. Left: Adult mouse mammary fat pad from nulliparous C57BL/6 mouse (4× and 10×, H&E staining). Right: H&E‐stained normal human breast tissue. Arrowhead and asterisks in right panel refer to loose intra‐ and dense interlobular stroma, respectively. Human histology images courtesy of Melissa Troester and the UNC Normal Breast Study (unpublished).
Figure 7. Figure 7. Adipose‐breast cancer interactions in mice and humans. (A) Early invasive lesions in H&E‐stained mammary gland tissue from the C3(1)‐TAg genetically engineered mouse model of spontaneous basal‐like breast cancer (unpublished images). (B) Human breast cancer—female, 50 years, lobular carcinoma, grade 1, Elston‐Ellis score 5. Image credit: The Human Protein Atlas (1,407).
Figure 8. Figure 8. Anatomical comparison of mouse (left) and human (right) prostate glands.
Figure 9. Figure 9. Desmoplasia and cancer‐associated adipocytes. (A) Mammary tumors from C3(1)‐TAg mice are stained with Hematoxylin/eosin (left) and Masson's trichrome (right) (unpublished). In tumors, chronic activation of the wound‐repair response results in desmoplasia, or excess collagenous extracellular matrix production, within tumors. Asterisks (*) indicate desmoplastic stroma. (B) Cancer‐associated adipocytes (black arrows) at or near the tumor invasive front become smaller and exhibit decreased expression of adipocyte markers, while the number of fibroblast‐like cells increases.
Figure 10. Figure 10. Obesity‐associated modifications in the adipose tissue microenvironment. Adipose tissue expansion in obesity occurs in association with extracellular matrix changes such as fibrosis. Adipocyte hypertrophy and hypoxia trigger macrophage infiltration and crown‐like structure formation, which further exacerbates development of fibrosis and inflammation.
Figure 11. Figure 11. HGF/cMET: an oncogenic signaling cascade. HGF secretion by stromal cells such as fibroblasts, adipocytes, and macrophages initiates an invasive growth program in epithelial cells.
Figure 12. Figure 12. Adipocyte subtypes and secreted factors. White adipocytes contain a large, unilocular lipid droplet and are specialized for storage of neutral lipids. Brown and/or beige adipocytes have increased mitochondrial content relative to white adipocytes and play important roles in thermogenesis. “Pink” adipocytes have been described in murine mammary gland, arising exclusively during pregnancy and lactation. Collectively, adipocytes secrete a broad range of signaling molecules.
Figure 13. Figure 13. Adipocytes promote tumor progression and metastasis. Adipocytes may provide metabolic substrates directly to cancer cells, or may indirectly influence cancer metabolism through exosome secretion. Adipocytes also secrete a variety of factors that promote tumor growth, EMT (epithelial‐mesenchymal transition), acquisition of stem‐like features, invasive behavior, and metastasis.
Figure 14. Figure 14. Obesity, cancer increase circulating ASCs. Human adipose tissue stroma is a rich source of multipotent ASCs, which enter the circulation and traffic to other tissues. This “shedding” process is increased in obese and/or tumor‐bearing individuals. Tumor chemokine secretion (e.g., CXCL1, CXCL8) is influenced by obesity and is implicated in ASC recruitment to developing tumors and differentiation into stromal populations such as fibroblasts, pericytes, and adipocytes.
Figure 15. Figure 15. Hypoxia & the angiogenic switch. An extensive list of proangiogenic factors is involved in both induction of the angiogenic switch in developing solid tumors and expansion of adipose tissue during progression to obesity. As tumor cells proliferate or adipocytes hypertrophy, hypoxia develops and triggers stabilization of the HIF‐1 complex, a transcription factor which promotes increased production of growth factors such as VEGF‐A, FGF1, TGF‐β, HGF, and angiopoietins 1 and 2. Additional proangiogenic factors include the adipokines leptin and adiponectin; cytokines such as TNFα, IL‐6, and IL‐8; and matrix metalloproteases, which degrade the extracellular matrix. Ultimately, increased vascularization alleviates regional hypoxia and facilitates further tissue expansion.
Figure 16. Figure 16. Mammary HGF/cMET signaling in the in C3(1)‐Tag mouse model of basal‐like breast cancer. Obesity increased HGF production by stromal cells, promoting tumor growth and angiogenesis. HGF/cMET‐mediated tumor promotion was reversible by weight loss or cMET inhibition.
Figure 17. Figure 17. Summary of changes in immune cell profile during progression to obesity. In the lean state, adipose tissue contains a variety of immunoregulatory cells such as M2‐like tissue‐resident macrophages, regulatory T cells, and eosinophils. Within days of exposure to an obesogenic diet neutrophils infiltrate adipose. Over weeks to months, an increase in CD8+ T cells, macrophages, and myeloid‐derived suppressor cells (MDSCs) results in a mix of pro‐ and anti‐inflammatory cells. In prolonged obesity, adipose mast cell content may also increase.
Figure 18. Figure 18. Macrophage activation as a spectrum. Unstimulated macrophages can be polarized in vitro to generate M1 (right) or M2 macrophages (left) using single cytokines or cytokine and other stimuli cocktails. However, tissue macrophages are exquisitely plastic, often expressing one or more markers of both M1 and M2 subtypes. Thus, tissue macrophage activation lies along a spectrum, resulting in mixed phenotype with specific expression and function varying by tissue type and timing of residence.
Figure 19. Figure 19. Adipose tissue macrophage ontogeny. Lineage tracing studies have revealed multiple embryonic sources for tissue‐resident macrophages (e.g., Kupffer cells, microglia) including the yolk sac and fetal liver. However, the contribution of bone marrow monocyte‐derived macrophages to tissue‐resident populations remains ambiguous. Moreover, the relative contribution of yolk sac, fetal liver, and bone marrow‐derived macrophages within adipose tissue depots has not been established, although the overall proportion of inflammatory, bone‐marrow derived macrophages increases in obese adipose.
Figure 20. Figure 20. Tumor‐Associated Neutrophils have N1 and N2‐like phenotypes. (A) Neutrophil content and phenotype is both pro‐ and anti‐tumoral with cytokines such as IFNβ, IL‐1β, TNF‐α activating the N1 or proinflammatory phenotype and TGF‐B driving the N2 immunomodulatory phenotype. The N1 neutrophil releases reactive oxygen species (ROS) and proteins that increase cell recruitment and extravasation [ICAM and CCL3 (MIP‐1‐alpha)]. N1 neutrophils support cytotoxic CD8+ T cell activity. N2 neutrophils have a less segmented nucleus than typical and secretes many angiogenic and immunosuppressive mediators, expressing arginase 1 for example. ROS secreted by both N1 and N2 may both promote genotoxicity in tumor initiation, or in contrast, can be cytotoxic to growing tumors. The timing and phenotype of neutrophil influx in obesity and tumor progression warrants further study. (B) Neutrophils infiltrate adipose early during progression to obesity. Neutrophil production of ROS, for example, through myeloperoxidase (MPO) expression, contributes to oxidative stress and fibrotic changes.
Figure 21. Figure 21. Mast cells: Unappreciated players in adipose and tumor biology. (A) Mast cell content in adipose tissue increases with obesity, with mast cells localized to blood vessels and/or within fibrotic bundles. Obesity is also associated with increased mast cell degranulation, an indicator of a mast cell activation. (B) In cancer, mast cells contribute to tumor progression through release of proangiogenic factors (MMP9, VEGF), immunosuppressive mediators (histamine), or growth factors such as PDGF. Mast cells also secrete cytokines that may promote (arrow) or inhibit (line) tumor progression. Mast cell influence on tumor progression appears to be dependent upon mast cell localization as peri‐ versus intratumoral.


Figure 1. Tumors as communities. Tumor cells coexist with a variety of stromal and immune cells, and reside in a complex mixture of signaling molecules and extracellular matrix components. Adjacent adipose tissue may provide a hospitable environment to developing tumors.


Figure 2. The adipose organ is comprised of several distinct adipose depots. Adipose depot locations and subtypes in (A) humans and (B) mice [panel B adapted from (85) with permission].


Figure 3. Approximate composition of human white adipose tissue stromal‐vascular fraction (percent cellularity).


Figure 4. Rising global and US obesity rates. (A) Global age‐adjusted prevalence of obesity in men and women, 1975 and 2014; (B) Class III obesity (BMI >40), globally and US; and (C) US obesity prevalence by race, ethnicity (270).


Figure 5. Comparison of mouse and human mammary gland anatomical structure. (A) Murine ductal elongation and branching occur at the Terminal End Buds (TEBs). (B) The human mammary gland is extensively branched, culminating in the functional terminal ductal lobular unit (TDLU).


Figure 6. Comparison of mouse and human mammary gland histology. Left: Adult mouse mammary fat pad from nulliparous C57BL/6 mouse (4× and 10×, H&E staining). Right: H&E‐stained normal human breast tissue. Arrowhead and asterisks in right panel refer to loose intra‐ and dense interlobular stroma, respectively. Human histology images courtesy of Melissa Troester and the UNC Normal Breast Study (unpublished).


Figure 7. Adipose‐breast cancer interactions in mice and humans. (A) Early invasive lesions in H&E‐stained mammary gland tissue from the C3(1)‐TAg genetically engineered mouse model of spontaneous basal‐like breast cancer (unpublished images). (B) Human breast cancer—female, 50 years, lobular carcinoma, grade 1, Elston‐Ellis score 5. Image credit: The Human Protein Atlas (1,407).


Figure 8. Anatomical comparison of mouse (left) and human (right) prostate glands.


Figure 9. Desmoplasia and cancer‐associated adipocytes. (A) Mammary tumors from C3(1)‐TAg mice are stained with Hematoxylin/eosin (left) and Masson's trichrome (right) (unpublished). In tumors, chronic activation of the wound‐repair response results in desmoplasia, or excess collagenous extracellular matrix production, within tumors. Asterisks (*) indicate desmoplastic stroma. (B) Cancer‐associated adipocytes (black arrows) at or near the tumor invasive front become smaller and exhibit decreased expression of adipocyte markers, while the number of fibroblast‐like cells increases.


Figure 10. Obesity‐associated modifications in the adipose tissue microenvironment. Adipose tissue expansion in obesity occurs in association with extracellular matrix changes such as fibrosis. Adipocyte hypertrophy and hypoxia trigger macrophage infiltration and crown‐like structure formation, which further exacerbates development of fibrosis and inflammation.


Figure 11. HGF/cMET: an oncogenic signaling cascade. HGF secretion by stromal cells such as fibroblasts, adipocytes, and macrophages initiates an invasive growth program in epithelial cells.


Figure 12. Adipocyte subtypes and secreted factors. White adipocytes contain a large, unilocular lipid droplet and are specialized for storage of neutral lipids. Brown and/or beige adipocytes have increased mitochondrial content relative to white adipocytes and play important roles in thermogenesis. “Pink” adipocytes have been described in murine mammary gland, arising exclusively during pregnancy and lactation. Collectively, adipocytes secrete a broad range of signaling molecules.


Figure 13. Adipocytes promote tumor progression and metastasis. Adipocytes may provide metabolic substrates directly to cancer cells, or may indirectly influence cancer metabolism through exosome secretion. Adipocytes also secrete a variety of factors that promote tumor growth, EMT (epithelial‐mesenchymal transition), acquisition of stem‐like features, invasive behavior, and metastasis.


Figure 14. Obesity, cancer increase circulating ASCs. Human adipose tissue stroma is a rich source of multipotent ASCs, which enter the circulation and traffic to other tissues. This “shedding” process is increased in obese and/or tumor‐bearing individuals. Tumor chemokine secretion (e.g., CXCL1, CXCL8) is influenced by obesity and is implicated in ASC recruitment to developing tumors and differentiation into stromal populations such as fibroblasts, pericytes, and adipocytes.


Figure 15. Hypoxia & the angiogenic switch. An extensive list of proangiogenic factors is involved in both induction of the angiogenic switch in developing solid tumors and expansion of adipose tissue during progression to obesity. As tumor cells proliferate or adipocytes hypertrophy, hypoxia develops and triggers stabilization of the HIF‐1 complex, a transcription factor which promotes increased production of growth factors such as VEGF‐A, FGF1, TGF‐β, HGF, and angiopoietins 1 and 2. Additional proangiogenic factors include the adipokines leptin and adiponectin; cytokines such as TNFα, IL‐6, and IL‐8; and matrix metalloproteases, which degrade the extracellular matrix. Ultimately, increased vascularization alleviates regional hypoxia and facilitates further tissue expansion.


Figure 16. Mammary HGF/cMET signaling in the in C3(1)‐Tag mouse model of basal‐like breast cancer. Obesity increased HGF production by stromal cells, promoting tumor growth and angiogenesis. HGF/cMET‐mediated tumor promotion was reversible by weight loss or cMET inhibition.


Figure 17. Summary of changes in immune cell profile during progression to obesity. In the lean state, adipose tissue contains a variety of immunoregulatory cells such as M2‐like tissue‐resident macrophages, regulatory T cells, and eosinophils. Within days of exposure to an obesogenic diet neutrophils infiltrate adipose. Over weeks to months, an increase in CD8+ T cells, macrophages, and myeloid‐derived suppressor cells (MDSCs) results in a mix of pro‐ and anti‐inflammatory cells. In prolonged obesity, adipose mast cell content may also increase.


Figure 18. Macrophage activation as a spectrum. Unstimulated macrophages can be polarized in vitro to generate M1 (right) or M2 macrophages (left) using single cytokines or cytokine and other stimuli cocktails. However, tissue macrophages are exquisitely plastic, often expressing one or more markers of both M1 and M2 subtypes. Thus, tissue macrophage activation lies along a spectrum, resulting in mixed phenotype with specific expression and function varying by tissue type and timing of residence.


Figure 19. Adipose tissue macrophage ontogeny. Lineage tracing studies have revealed multiple embryonic sources for tissue‐resident macrophages (e.g., Kupffer cells, microglia) including the yolk sac and fetal liver. However, the contribution of bone marrow monocyte‐derived macrophages to tissue‐resident populations remains ambiguous. Moreover, the relative contribution of yolk sac, fetal liver, and bone marrow‐derived macrophages within adipose tissue depots has not been established, although the overall proportion of inflammatory, bone‐marrow derived macrophages increases in obese adipose.


Figure 20. Tumor‐Associated Neutrophils have N1 and N2‐like phenotypes. (A) Neutrophil content and phenotype is both pro‐ and anti‐tumoral with cytokines such as IFNβ, IL‐1β, TNF‐α activating the N1 or proinflammatory phenotype and TGF‐B driving the N2 immunomodulatory phenotype. The N1 neutrophil releases reactive oxygen species (ROS) and proteins that increase cell recruitment and extravasation [ICAM and CCL3 (MIP‐1‐alpha)]. N1 neutrophils support cytotoxic CD8+ T cell activity. N2 neutrophils have a less segmented nucleus than typical and secretes many angiogenic and immunosuppressive mediators, expressing arginase 1 for example. ROS secreted by both N1 and N2 may both promote genotoxicity in tumor initiation, or in contrast, can be cytotoxic to growing tumors. The timing and phenotype of neutrophil influx in obesity and tumor progression warrants further study. (B) Neutrophils infiltrate adipose early during progression to obesity. Neutrophil production of ROS, for example, through myeloperoxidase (MPO) expression, contributes to oxidative stress and fibrotic changes.


Figure 21. Mast cells: Unappreciated players in adipose and tumor biology. (A) Mast cell content in adipose tissue increases with obesity, with mast cells localized to blood vessels and/or within fibrotic bundles. Obesity is also associated with increased mast cell degranulation, an indicator of a mast cell activation. (B) In cancer, mast cells contribute to tumor progression through release of proangiogenic factors (MMP9, VEGF), immunosuppressive mediators (histamine), or growth factors such as PDGF. Mast cells also secrete cytokines that may promote (arrow) or inhibit (line) tumor progression. Mast cell influence on tumor progression appears to be dependent upon mast cell localization as peri‐ versus intratumoral.
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Teaching Material

A. J. Cozzo, A. M. Fuller, L. Makowski. Contribution of Adipose Tissue to Development of Cancer. Compr Physiol. 8: 2018, 237-282.

Didactic Synopsis

Major Teaching Points:

  1. Solid tumor growth requires the interaction of tumor cells with the surrounding tissue, leading to a view of tumors as communities rather than exclusively tumor cells.
  2. Adipose tissue, or fat, plays important roles in cancer risk and outcome because many tumors grow close to or in direct contact with adipose.
  3. The adipose community—or microenvironment—includes adipocytes and adipose-associated stromal and vascular components, such as fibroblasts and other connective tissue cells, stem cells, endothelial cells, innate and adaptive immune cells, and extracellular signaling and matrix components.
  4. Herein, we review the cellular and noncellular parts of the adipose “organ” and the mechanisms by which varied microenvironmental components contribute to tumor development, with emphasis on obesity.
  5. Obesity dramatically modifies the adipose tissue microenvironment in numerous ways, which intriguingly resemble shifts observed within the tumor microenvironment.
  6. Understanding neighboring adipose is critical in tumorigenesis.

Didactic Legends

The figures—in a freely downloadable PowerPoint format—can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching.

Figure 1. Tumors as communities.

Teaching point(s):

  • Tumor cells grow in the context of immune cells, stromal cells, and noncellular extracellular matrix.
  • Adjacent adipose (fat) tissue may influence tumor growth.

Figure 2. The adipose organ is comprised of several distinct adipose depots.

This figure illustrates that there are different types of adipose depots in humans and mice with many conserved similarities between species.

Figure 3. Approximate composition of human white adipose tissue stromal-vascular fraction (percent cellularity).

This figure illustrates the proportions of the primary cells in human adipose tissue with immune cells being the most represented.

Figure 4. Rising global and US obesity rates.

Teaching point(s):

  • Obesity has increased globally over 4 decades with women having higher prevalence of obesity than men.
  • Morbid or class III obesity is highly prevalent in the US compared to globally, with higher prevalence in women compared to men.
  • Non-Hispanic black women have the greatest prevalence of obesity.

Figure 5. Comparison of mouse and human mammary gland anatomical structure.

Teaching point(s):

  • The mouse mammary gland elongates and branches at Terminal End Buds (TEBs).
  • The human mammary gland ends in the functional terminal ductal lobular unit (TDLU).

Figure 6: Comparison of mouse and human mammary gland histology.

This figure illustrates similarities and differences between mouse mammary fat pad and normal human breast. The human breast has greater stromal content and fewer adipocytes.

Figure 7. Adipose-breast cancer interactions in mice and humans.

This figure illustrates how tumors can grow near or invade into adjacent adipose tissue.

Figure 8. Anatomical comparison of mouse (left) and human (right) prostate glands.

This figure illustrates that the prostate surrounds the bladder in both humans and mice, yet the lobes, or zones, are anatomically different between species.

Figure 9. Desmoplasia and cancer-associated adipocytes.

Teaching points:

  • In tumors, chronic activation of the wound-repair response results in desmoplasia, or excess collagenous extracellular matrix production, within tumors. Asterisks (*) indicate desmoplastic stroma.
  • Cancer-associated adipocytes (black arrows) at or near the tumor invasive front become smaller and exhibit decreased expression of adipocyte markers, while the number of fibroblast-like cells increases.

Figure 10. Obesity-associated modifications in the adipose tissue microenvironment.

Teaching points:

  • Adipose tissue expansion in obesity occurs in association with extracellular matrix changes such as fibrosis.
  • Adipocyte hypertrophy and hypoxia trigger macrophage infiltration and crown-like structure formation.
  • Fibrosis and inflammation characterize obese adipose tissue.

Figure 11. HGF/cMET: an oncogenic signaling cascade.

Teaching points:

  • Growth factors such as hepatocyte growth factor (HGF) are secreted by stromal cells such as fibroblasts, adipocytes, and macrophages.
  • HGF initiates a growth program in epithelial cells leading to cancer and metastasis.

Figure 12. Adipocyte subtypes and secreted factors.

Teaching points:

  • There are several types of adipocytes.
  • White adipocytes contain a large, unilocular lipid droplet and are specialized for storage of neutral lipids.
  • Brown and/or beige adipocytes have increased mitochondrial content relative to white adipocytes and play important roles in thermogenesis.
  • “Pink” adipocytes have been described in murine mammary gland, arising exclusively during pregnancy and lactation.
  • Depending on depot and metabolic state, adipocytes secrete a broad range of signaling molecules.

Figure 13. Adipocytes promote tumor progression and metastasis.

Teaching points:

  • Adipocytes within the tumor mass are termed cancer-associated adipocytes (also referred to as peritumoral, intratumoral, or tumor-infiltrating adipocytes.
  • Cancer associated adipocytes secrete proteins, metabolites, and exosomes that can alter cancer cell biology.
  • Cancer associated adipocytes also secrete a variety of factors that promote tumor growth, epithelial-mesenchymal transition (EMT), acquisition of stem-like features, invasive behavior, and metastasis.

Figure 14. Obesity, cancer increase circulating adipose stromal cells (ASCs).

This cartoon illustrates that ASCs are multipotent stem cells that increase with obesity and traffic to tumors to increase tumor growth and angiogenesis.

Figure 15. Hypoxia and the angiogenic switch.

Teaching points:

  • Commonalities between expanding adipose and a growing tumor exist, and include the necessity for increased vascularization and production of proangiogenic factors.
  • Hypoxia develops and triggers release of many growth factors and other cytokines that enable blood vessel growth, a process known as the “angiogenic switch.”
  • Increased vascularization alleviates regional hypoxia and facilitates further tissue expansion of the adipose depot or tumor.

Figure 16. Mammary HGF/cMET signaling in the in C3(1)-Tag mouse model of basal-like breast cancer.

Teaching points:

  • Obesity increased HGF production by stromal cells, promoting tumor growth and angiogenesis.
  • HGF/cMET-mediated tumor promotion was reversible by weight loss or cMET inhibition.

Figure 17. Summary of changes in immune cell profile during progression to obesity.

Teaching points:

  • Changes in immune cell populations from days to weeks to months after obesogenic high fat diet exposure are shown.
  • Immunoregulatory cells such as tissue-resident macrophages, regulatory T cells, and eosinophils are present in the lean state at the start of the timeline but prevalence declines with obesity.
  • Within days of exposure to an obesogenic diet neutrophils infiltrate adipose.
  • Over weeks to months, an increase in CD8 + T cells, macrophages, and myeloid-derived suppressor cells (MDSCs) results in a mix of pro- and anti-inflammatory cells.
  • In prolonged obesity, adipose mast cell content may also increase.

Figure 18. Macrophage activation as a spectrum.

Teaching points:

  • Tissue macrophages have multiple sources. Some macrophages seed tissues during fetal development and self-maintain through proliferation, while others infiltrate tissue as monocyte-derived macrophages.
  • Unstimulated macrophages can be stimulated in vitro to generate M1 macrophages (right) or M2 macrophages (left) using single cytokines or cocktails of cytokines plus other stimuli.
  • However, tissue macrophages in vivo lie along a spectrum and are exquisitely plastic, often expressing one or more markers of both “M1” and “M2” subtypes.
  • Macrophage functions and phenotypes in tissues vary by tissue type and timing of residence.

Fig. 19. Adipose tissue macrophage ontogeny.

Teaching points:

  • Tissue-resident macrophages (e.g., Kupffer cells, microglia) are derived from embryonic sites including the yolk sac and fetal liver.
  • The relative contribution of yolk sac, fetal liver, and bone marrow-derived macrophages within adipose tissue depots has not been established.
  • It is established that inflammatory, bone-marrow-derived macrophages increase in obese adipose.

Figure 20. Tumor-Associated Neutrophils have N1 and N2-like phenotypes.

Teaching points:

  • This cartoon illustrates that like macrophages, there are varied neutrophil phenotypes that are considered both pro- and antitumoral.
  • N1 neutrophils support cytotoxic CD8 + T cell activity that would limit tumor progression.
  • N2 neutrophils secrete many angiogenic and immunosuppressive mediators to support tumor growth.
  • ROS secreted by both N1 and N2 may both promote genotoxicity in tumor initiation, or in contrast, can be cytotoxic to growing tumors.
  • Neutrophil production of reactive oxygen species, for example, through myeloperoxidase (MPO) expression, contributes to oxidative stress and fibrotic changes.

Figure 21. Mast cells: Unappreciated players in adipose and tumor biology.

Teaching points:

  • Mast cell content and activation (degranulation) increases with obesity in adipose tissue.
  • Mast cells contribute to tumor progression through factors that drive growth and angiogenesis, or cause immunosuppression to facilitate tumor immune evasion. However, some mast cell-derived factors also limit tumor growth.

 


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Article Title: Contribution of Adipose Tissue to Development of Cancer
 

How to Cite

Alyssa J. Cozzo, Ashley M. Fuller, Liza Makowski. Contribution of Adipose Tissue to Development of Cancer. Compr Physiol 2017, 8: 237-282. doi: 10.1002/cphy.c170008