Parallel accumulation of tumor hyaluronan, collagen, and other drivers of tumor progression

Xiaoming Li, H. Michael Shepard, Jessica A. Cowell, Chunmei Zhao, Ryan J. Osgood, Sanna Rosengren, Barbara Blouw, Sheryl A. Garrovillo, Mark "Marty" Pagel, Clifford J. Whatcott, Haiyong Han, Daniel D. Von Hoff, Darin M. Taverna, Michael J. LaBarre, Daniel C. Maneval, Curtis B. Thompson

Research output: Contribution to journalArticle

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Abstract

Purpose: The tumor microenvironment (TME) evolves to support tumor progression. One marker of more aggressive malignancy is hyaluronan (HA) accumulation. Here, we characterize biological and physical changes associated with HA-accumulating (HA-high) tumors. Experimental Design: We used immunohistochemistry, in vivo imaging of tumor pH, and microdialysis to characterize the TME of HA-high tumors, including tumor vascular structure, hypoxia, tumor perfusion by doxorubicin, pH, content of collagen. and smooth muscle actin (a-SMA). A novel method was developed to measure real-time tumor-associated soluble cytokines and growth factors. We also evaluated biopsies of murine and pancreatic cancer patients to investigate HA and collagen content, important contributors to drug resistance. Results: In immunodeficient and immunocompetent mice, increasing tumor HA content is accompanied by increasing collagen content, vascular collapse, hypoxia, and increased metastatic potential, as reflected by increased a-SMA. In vivo treatment of HA-high tumors with PEGylated recombinant human hyaluronidase (PEGPH20) dramatically reversed these changes and depleted stores of VEGF-A165, suggesting that PEGPH20 may also diminish the angiogenic potential of the TME. Finally, we observed in xenografts and in pancreatic cancer patients a coordinated increase in HA and collagen tumor content. Conclusions: The accumulation of HA in tumors is associated with high tIP, vascular collapse, hypoxia, and drug resistance. These findings may partially explain why more aggressive malignancy is observed in the HA-high phenotype. We have shown that degradation of HA by PEGPH20 partially reverses this phenotype and leads to depletion of tumor-associated VEGF-A165. These results encourage further clinical investigation of PEGPH20.

Original languageEnglish (US)
Pages (from-to)4798-4807
Number of pages10
JournalClinical Cancer Research
Volume24
Issue number19
DOIs
StatePublished - Oct 1 2018
Externally publishedYes

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Hyaluronic Acid
Collagen
Neoplasms
Tumor Microenvironment
Blood Vessels
Pancreatic Neoplasms
Drug Resistance
Vascular Endothelial Growth Factor A
Smooth Muscle
Actins
Phenotype
Hyaluronoglucosaminidase
Microdialysis
Heterografts
Doxorubicin
Intercellular Signaling Peptides and Proteins
Research Design
Perfusion
Immunohistochemistry
Cytokines

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Li, X., Michael Shepard, H., Cowell, J. A., Zhao, C., Osgood, R. J., Rosengren, S., ... Thompson, C. B. (2018). Parallel accumulation of tumor hyaluronan, collagen, and other drivers of tumor progression. Clinical Cancer Research, 24(19), 4798-4807. https://doi.org/10.1158/1078-0432.CCR-17-3284

Parallel accumulation of tumor hyaluronan, collagen, and other drivers of tumor progression. / Li, Xiaoming; Michael Shepard, H.; Cowell, Jessica A.; Zhao, Chunmei; Osgood, Ryan J.; Rosengren, Sanna; Blouw, Barbara; Garrovillo, Sheryl A.; Pagel, Mark "Marty"; Whatcott, Clifford J.; Han, Haiyong; Von Hoff, Daniel D.; Taverna, Darin M.; LaBarre, Michael J.; Maneval, Daniel C.; Thompson, Curtis B.

In: Clinical Cancer Research, Vol. 24, No. 19, 01.10.2018, p. 4798-4807.

Research output: Contribution to journalArticle

Li, X, Michael Shepard, H, Cowell, JA, Zhao, C, Osgood, RJ, Rosengren, S, Blouw, B, Garrovillo, SA, Pagel, MM, Whatcott, CJ, Han, H, Von Hoff, DD, Taverna, DM, LaBarre, MJ, Maneval, DC & Thompson, CB 2018, 'Parallel accumulation of tumor hyaluronan, collagen, and other drivers of tumor progression', Clinical Cancer Research, vol. 24, no. 19, pp. 4798-4807. https://doi.org/10.1158/1078-0432.CCR-17-3284
Li X, Michael Shepard H, Cowell JA, Zhao C, Osgood RJ, Rosengren S et al. Parallel accumulation of tumor hyaluronan, collagen, and other drivers of tumor progression. Clinical Cancer Research. 2018 Oct 1;24(19):4798-4807. https://doi.org/10.1158/1078-0432.CCR-17-3284
Li, Xiaoming ; Michael Shepard, H. ; Cowell, Jessica A. ; Zhao, Chunmei ; Osgood, Ryan J. ; Rosengren, Sanna ; Blouw, Barbara ; Garrovillo, Sheryl A. ; Pagel, Mark "Marty" ; Whatcott, Clifford J. ; Han, Haiyong ; Von Hoff, Daniel D. ; Taverna, Darin M. ; LaBarre, Michael J. ; Maneval, Daniel C. ; Thompson, Curtis B. / Parallel accumulation of tumor hyaluronan, collagen, and other drivers of tumor progression. In: Clinical Cancer Research. 2018 ; Vol. 24, No. 19. pp. 4798-4807.
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T1 - Parallel accumulation of tumor hyaluronan, collagen, and other drivers of tumor progression

AU - Li, Xiaoming

AU - Michael Shepard, H.

AU - Cowell, Jessica A.

AU - Zhao, Chunmei

AU - Osgood, Ryan J.

AU - Rosengren, Sanna

AU - Blouw, Barbara

AU - Garrovillo, Sheryl A.

AU - Pagel, Mark "Marty"

AU - Whatcott, Clifford J.

AU - Han, Haiyong

AU - Von Hoff, Daniel D.

AU - Taverna, Darin M.

AU - LaBarre, Michael J.

AU - Maneval, Daniel C.

AU - Thompson, Curtis B.

PY - 2018/10/1

Y1 - 2018/10/1

N2 - Purpose: The tumor microenvironment (TME) evolves to support tumor progression. One marker of more aggressive malignancy is hyaluronan (HA) accumulation. Here, we characterize biological and physical changes associated with HA-accumulating (HA-high) tumors. Experimental Design: We used immunohistochemistry, in vivo imaging of tumor pH, and microdialysis to characterize the TME of HA-high tumors, including tumor vascular structure, hypoxia, tumor perfusion by doxorubicin, pH, content of collagen. and smooth muscle actin (a-SMA). A novel method was developed to measure real-time tumor-associated soluble cytokines and growth factors. We also evaluated biopsies of murine and pancreatic cancer patients to investigate HA and collagen content, important contributors to drug resistance. Results: In immunodeficient and immunocompetent mice, increasing tumor HA content is accompanied by increasing collagen content, vascular collapse, hypoxia, and increased metastatic potential, as reflected by increased a-SMA. In vivo treatment of HA-high tumors with PEGylated recombinant human hyaluronidase (PEGPH20) dramatically reversed these changes and depleted stores of VEGF-A165, suggesting that PEGPH20 may also diminish the angiogenic potential of the TME. Finally, we observed in xenografts and in pancreatic cancer patients a coordinated increase in HA and collagen tumor content. Conclusions: The accumulation of HA in tumors is associated with high tIP, vascular collapse, hypoxia, and drug resistance. These findings may partially explain why more aggressive malignancy is observed in the HA-high phenotype. We have shown that degradation of HA by PEGPH20 partially reverses this phenotype and leads to depletion of tumor-associated VEGF-A165. These results encourage further clinical investigation of PEGPH20.

AB - Purpose: The tumor microenvironment (TME) evolves to support tumor progression. One marker of more aggressive malignancy is hyaluronan (HA) accumulation. Here, we characterize biological and physical changes associated with HA-accumulating (HA-high) tumors. Experimental Design: We used immunohistochemistry, in vivo imaging of tumor pH, and microdialysis to characterize the TME of HA-high tumors, including tumor vascular structure, hypoxia, tumor perfusion by doxorubicin, pH, content of collagen. and smooth muscle actin (a-SMA). A novel method was developed to measure real-time tumor-associated soluble cytokines and growth factors. We also evaluated biopsies of murine and pancreatic cancer patients to investigate HA and collagen content, important contributors to drug resistance. Results: In immunodeficient and immunocompetent mice, increasing tumor HA content is accompanied by increasing collagen content, vascular collapse, hypoxia, and increased metastatic potential, as reflected by increased a-SMA. In vivo treatment of HA-high tumors with PEGylated recombinant human hyaluronidase (PEGPH20) dramatically reversed these changes and depleted stores of VEGF-A165, suggesting that PEGPH20 may also diminish the angiogenic potential of the TME. Finally, we observed in xenografts and in pancreatic cancer patients a coordinated increase in HA and collagen tumor content. Conclusions: The accumulation of HA in tumors is associated with high tIP, vascular collapse, hypoxia, and drug resistance. These findings may partially explain why more aggressive malignancy is observed in the HA-high phenotype. We have shown that degradation of HA by PEGPH20 partially reverses this phenotype and leads to depletion of tumor-associated VEGF-A165. These results encourage further clinical investigation of PEGPH20.

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