Matrix remodeling stimulates stromal autophagy, “fueling” cancer cell mitochondrial metabolism and metastasis

Abstract

We have previously demonstrated that loss of stromal caveolin-1 (Cav-1) in cancer-associated fibroblasts is a strong and independent predictor of poor clinical outcome in human breast cancer patients. However, the signaling mechanism(s) by which Cav-1 downregulation leads to this tumor-promoting microenvironment are not well understood. To address this issue, we performed an unbiased comparative proteomic analysis of wild-type (WT) and Cav-1(-/-) null mammary stromal fibroblasts (MSFs). Our results show that plasminogen activator inhibitor type 1 and type 2 (PAI-1 and PAI-2) expression is significantly increased in Cav-1(-/-) MSFs. To establish a direct cause-effect relationship, we next generated immortalized human fibroblast lines stably overexpressing either PAI-1 or PAI-2. Importantly, PAI-1/2(+) fibroblasts promote the growth of MDA-MB-231 tumors (a human breast cancer cell line) in a murine xenograft model, without any increases in angiogenesis. Similarly, PAI-1/2(+) fibroblasts stimulate experimental metastasis of MDA-MB-231 cells using an in vivo lung colonization assay. Further mechanistic studies revealed that fibroblasts overexpressing PAI-1 or PAI-2 display increased autophagy ("self-eating") and are sufficient to induce mitochondrial biogenesis/activity in adjacent cancer cells, in co-culture experiments. In xenografts, PAI-1/2(+) fibroblasts significantly reduce the apoptosis of MDA-MB-231 tumor cells. The current study provides further support for the "Autophagic Tumor Stroma Model of Cancer" and identifies a novel "extracellular matrix"-based signaling mechanism, by which a loss of stromal Cav-1 generates a metastatic phenotype. Thus, the secretion and remodeling of extracellular matrix components (such as PAI-1/2) can directly regulate both (1) autophagy in stromal fibroblasts and (2) epithelial tumor cell mitochondrial metabolism.

Absence of caveolin-1 alters heat shock protein expression in spontaneous mammary tumors driven by Her-2/neu expression

“…Other proteins also contribute to apoptosis resistance in this tumor model. Castello-Cros et al (2011) reported that the stromal fibroblasts lacking Cav-1 significantly increased plasminogen activator inhibitor type 1 and type 2 (PAI-1 and PAI-2) expression and that in xenografts, co-inoculation with fibroblasts that stably express either PAI-1 or PAI-2 significantly reduced the extent of apoptosis of MDA-MB-231 human breast tumors. Finally, we cannot rule out the possibility that Hsp70 is also playing another role apart from the suppression of apoptosis.…”

Melanoma Cells Block PEDF Production in Fibroblasts to Induce the Tumor-Promoting Phenotype of Cancer-Associated Fibroblasts

“…Most interesting, SERPINB2 (Plasminogen Activator Inhibitor 2) functions as a tumor suppressor, when expressed by cancer cells (49) but becomes a clear-cut oncogene if expressed by fibroblasts. In breast cancer models, it contributes to the formation of autophagic stroma, which fuels mitochondrial metabolism in cancer cells and promotes metastasis (50) or enables cancer cell survival and vascular cooption in the brain (51). …”

Autophagy in stem cells

“…175 Indeed, the increased glycolysis due to enhanced mitochondrial turnover generates excessive stromal cell lactate and ketones, which are secreted into the intracellular space. 176 The cancer cells then take up the high-energy metabolites (lactate and ketones) and use them to feed cancer cell mitochondrial energy production and generate mitochondrial precursors for the biogenesis of new cancer cells. Lactate and ketones from the autophagic tumor stroma increase the transcriptional expression of gene profiles normally associated with stemness, including genes commonly upregulated in embryonic stem cells, and may therefore promote the dynamic appearance of CSC cellular states, resulting in significant decreases in patient survival.…”