Acidic Pericellular Ph: Effects On Proteolysis And Gene Expression As Determined In 3d Models Of Breast Carcinoma

<p>Among the non-cellular microenvironmental factors that contribute to malignancy of solid tumors is an acidic peritumoral pH. The first objective was to determine if an acidic extracellular pH observed in vivo (i.e., pHe 6.8) affects the activity of proteases, such as cathepsin B, that contribute to degradation of collagen IV by tumor cells when grown in biologically relevant three-dimensional cultures. At pHe 6.8 there were increases in pericellular active cysteine cathepsins and in degradation of DQ-collagen IV, which was partially blocked by a cathepsin B inhibitor. Imaging probes for active cysteine cathepsins localized to tumors in vivo. The amount of bound probe decreased in tumors in bicarbonate-treated mice, a treatment previously shown to increase peritumoral pHe and reduce local invasion of the tumors. Our results are consistent with the acid-mediated invasion hypothesis and with a role for cathepsin B in promoting degradation of a basement membrane protein substrate, i.e. type IV collagen, in an acidic peritumoral environment. The second objective was to use a microarray approach to identify significantly altered genes that may be of importance in the response to acidic pH in ductal carcinoma in situ (DCIS). We have found that STAT1-directed signaling is up-regulated in response to acidic pH extracellularly. Its role in altering glycolytic pathways suggests an important role for this transcription factor in the development of an acidic extracellular pH.</p>

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Open Access Dissertation

Discipline thesis:degree_discipline

Cancer Biology

Year dc:date.available

2013

Author dc:creator

• Rothberg, Jennifer M.

Contributors dc:contributor

• Bonnie F. Sloane

• 3D culture
• acidic pH
• breast cancer
• live-cell imaging
• proteolysis
• STAT1
• Cell Biology
• Molecular Biology
• Pharmacology

Repository record dc:identifier

https://digitalcommons.wayne.edu/oa_dissertations/694

OAI identifier oai:identifier

oai:digitalcommons.wayne.edu:oa_dissertations-1693