Acid-mediated tumor proteolysis: contribution of cysteine cathepsins.

One of the noncellular microenvironmental factors that contribute to malignancy of solid tumors is acidic peritumoral pH. We have previously demonstrated that extracellular acidosis leads to localization of the cysteine pro-tease cathepsin B on the tumor cell membrane and its secretion. The objective of the present study was to determine if an acidic extracellular pH such as that observed in vivo (i.

Acidity generated by the tumor microenvironment drives local invasion.

The pH of solid tumors is acidic due to increased fermentative metabolism and poor perfusion. It has been hypothesized that acid pH promotes local invasive growth and metastasis. The hypothesis that acid mediates invasion proposes that H(+) diffuses from the proximal tumor microenvironment into adjacent normal tissues where it causes tissue remodeling that permits local invasion.

Chronic autophagy is a cellular adaptation to tumor acidic pH microenvironments.

Tumor cell survival relies upon adaptation to the acidic conditions of the tumor microenvironment. To investigate potential acidosis survival mechanisms, we examined the effect of low pH (6.7) on human breast carcinoma cells.

3D/4D functional imaging of tumor-associated proteolysis: impact of microenvironment.

Proteases play causal roles in many aspects of the aggressive phenotype of tumors, yet many of the implicated proteases originate from tumor-associated cells or from responses of tumor cells to interactions with other cells. Therefore, to obtain a comprehensive view of tumor proteases, we need to be able to assess proteolysis in tumors that are interacting with their microenvironment. As this is difficult to do in vivo, we have developed functional live-cell optical imaging assays and 3D and 4D (i.

Live-cell imaging of tumor proteolysis: impact of cellular and non-cellular microenvironment.

Our laboratory has had a longstanding interest in how the interactions between tumors and their microenvironment affect malignant progression. Recently, we have focused on defining the proteolytic pathways that function in the transition of breast cancer from the pre-invasive lesions of ductal carcinoma in situ (DCIS) to invasive ductal carcinomas (IDCs). We use live-cell imaging to visualize, localize and quantify proteolysis as it occurs in real-time and thereby have established roles for lysosomal cysteine proteases both pericellularly and intracellularly in tumor proteolysis.