Abstract
Cancer cells grow in highly complex stromal microenvironments, which through metabolic remodelling, catabolism, autophagy and inflammation nurture them and are able to facilitate metastasis and resistance to therapy. However, these changes in the metabolic profile of stromal cancer-associated fibroblasts and their impact on cancer initiation, progression and metastasis are not well-known. This is the first study to provide a comprehensive proteomic portrait of the azathioprine and taxol-induced catabolic state on human stromal fibroblasts, which comprises changes in the expression of metabolic enzymes, myofibroblastic differentiation markers, antioxidants, proteins involved in autophagy, senescence, vesicle trafficking and protein degradation, and inducers of inflammation. Interestingly, many of these features are major contributors to the aging process. A catabolic stroma signature, generated with proteins found differentially up-regulated in taxol-treated fibroblasts, strikingly correlates with recurrence, metastasis and poor patient survival in several solid malignancies. We therefore suggest the inhibition of the catabolic state in healthy cells as a novel approach to improve current chemotherapy efficacies and possibly avoid future carcinogenic processes.
Highlights
Unlike normal healthy fibroblasts, aged or senescent fibroblasts are pro-tumorigenic [1]
To identify differentially regulated proteins upon chemotherapeutic treatment, hTERT-BJ1 fibroblasts were exposed for 48 h to either vehicle or sub-lethal concentrations of azathioprine (100 μM) or taxol (100 nM) (Figure S1), and cell lysates were subject to labelfree quantitative proteomics
We have showed in a previous study that several chemotherapeutic agents, including azathioprine and taxol were able to stimulate stromal fibroblasts to consume more glucose and produce more lactate, which was released via enhanced Monocarboxylate transporter 4 (MCT4) expression, increasing extracellular acidification (Figure 1)
Summary
Unlike normal healthy fibroblasts, aged or senescent fibroblasts are pro-tumorigenic [1]. Cellular damage, which is widely considered to be the general cause of aging, occasionally may provide cells with abnormal advantages that can eventually give rise to cancer. Cancer and aging are two different faces of the same underlying process: the accumulation of cellular damage in cells and tissues over the years, which eventually become senescent. Accumulation of senescent cells has been detected after examination of aged tissues, and it contributes to tissue degeneration during aging [1]. Senescent cells can have profound effects on the surrounding microenvironment, through the expression and secretion of a range of pro-inflammatory factors, which is known as the senescence-associated secretory phenotype (SASP). The onset of SASP may help explain the increased tumor incidence observed in aged individuals [2]
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