On the Pro-Metastatic Stress Response to Cancer Therapies: Evidence for a Positive Co-Operation between TIMP-1, HIF-1α, and miR-210

Abstract

In contrast to expectations in the past that tumor starvation or unselective inhibition of proteolytic activity would cure cancer, there is accumulating evidence that microenvironmental stress, such as hypoxia or broad-spectrum inhibition of metalloproteinases can promote metastasis. In fact, malignant tumor cells, due to their genetic and epigenetic instability, are predisposed to react to stress by adaptation and, if the stress persists, by escape and formation of metastasis. Recent recognition of the concepts of dynamic evolution as well as population and systems biology is extremely helpful to understand the disappointments of clinical trials with new drugs and may lead to paradigm-shifts in therapy strategies. This must be complemented by an increased understanding of molecular mechanism involved in stress response. Here, we review new roles of Hypoxia-inducible factor-1 (HIF-1), one transcription factor regulating stress response-related gene expression: HIF-1 is crucial for invasion and metastasis, independent from its pro-survival function. In addition, HIF-1 mediates pro-metastatic microenvironmental changes of the proteolytic balance as triggered by high systemic levels of tissue inhibitor of metalloproteinases-1 (TIMP-1), typical for many aggressive cancers, and regulates the metabolic switch to glycolysis, notably via activation of the microRNA miR-210. There is preliminary evidence that TIMP-1 also induces miR-210. Such positive-regulatory co-operation of HIF-1α, miR-210, and TIMP-1, all described to correlate with bad prognosis of cancer patients, opens new perspectives of gaining insight into molecular mechanisms of metastasis-inducing evasion of tumor cells from stress.

Molecular targets and pathways involved in liver metastasis of colorectal cancer

“…In fact, we recently found that TIMP1 induces HIF1a and miR-210 in tumor cells in vitro via CD63, resulting in increased tumorigenicity of the cells [62]. HIF-1a as a mediator of the hypoxic state promotes pro-invasive mechanisms by upregulation of miR-210 which inhibits respiration by inhibition of the subunit D of the succinate dehydrogenase complex (SDHD), regulates the switch to anaerobic glycolysis and induces cell-cycle arrest by inhibition of transcription factor E2F3 in vitro [61][62][63].…”

TIMP-1 signaling via CD63 triggers granulopoiesis and neutrophilia in mice

“…9 Due to this two-pronged functional activity, TIMP-1 exerts a wide range of effects on tissue homeostasis, as well as cell behavior including inhibition of apoptosis, 13 promotion of cell proliferation and differentiation or the metastatic potential of tumor cells. 14,15 Separate investigation of the two functions of TIMP-1 can be achieved by employing variants either lacking the C-terminus (N-TIMP-1 9 ) or with mutations in the N-terminal domain that diminish protease binding but retain signaling capacity (TIMP-1/T2G, 16 vvTIMP-1 17 ). Although investigation of such variants helped to explain physiological effects of TIMP-1 in vitro, so far only limited knowledge is available on the relevance of signaling or protease inhibition for tissue homeostasis.…”

1α,25(OH)2D3 differentially regulates miRNA expression in human bladder cancer cells

“…These genes regulate inflammation, wound healing and angiogenesis which ultimately lead to metastasis (39). Stress in the tumor microenvironment such as hypoxia encourages metastasis (40). Increased hypoxia-inducible factor-1 (HIF-1) in hypoxia condition promotes tumor invasiveness and metastasis (40).…”

“…Stress in the tumor microenvironment such as hypoxia encourages metastasis (40). Increased hypoxia-inducible factor-1 (HIF-1) in hypoxia condition promotes tumor invasiveness and metastasis (40). Besides local stress, systemic stress can also promote metastasis.…”