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Alterations of Ion Homeostasis in Cancer Metastasis: Implications for Treatment.

ABSTRACT: We have previously reported that metastases from all malignancies are characterized by a core program of gene expression that suppresses extracellular matrix interactions, induces vascularization/tissue remodeling, activates the oxidative metabolism, and alters ion homeostasis. Among these features, the least elucidated component is ion homeostasis. Here we review the literature with the goal to infer a better mechanistic understanding of the progression-associated ionic alterations and identify the most promising drugs for treatment. Cancer metastasis is accompanied by skewing in calcium, zinc, copper, potassium, sodium and chloride homeostasis. Membrane potential changes and water uptake through Aquaporins may also play roles. Drug candidates to reverse these alterations are at various stages of testing, with some having entered clinical trials. Challenges to their utilization comprise differences among tumor types and the involvement of multiple ions in each case. Further, adverse effects may become a concern, as channel blockers, chelators, or supplemented ions will affect healthy and transformed cells alike.

SUBMITTER: Fnu G

PROVIDER: S-EPMC8721045 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Alterations of Ion Homeostasis in Cancer Metastasis: Implications for Treatment.

Fnu Gulimirerouzi G Weber Georg F GF

Frontiers in oncology 20211220

We have previously reported that metastases from all malignancies are characterized by a core program of gene expression that suppresses extracellular matrix interactions, induces vascularization/tissue remodeling, activates the oxidative metabolism, and alters ion homeostasis. Among these features, the least elucidated component is ion homeostasis. Here we review the literature with the goal to infer a better mechanistic understanding of the progression-associated ionic alterations and identify ...[more]

PMID: 34988012

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Project description:Cancer remains the second leading cause of mortality worldwide. In the course of this multistage and multifactorial disease, a set of alterations takes place, with genetic and environmental factors modulating tumorigenesis and disease progression. Metabolic alterations of tumors are well-recognized and are considered as one of the hallmarks of cancer. Cancer cells adapt their metabolic competences in order to efficiently supply their novel demands of energy to sustain cell proliferation and metastasis. At present, there is a growing interest in understanding the metabolic switch that occurs during tumorigenesis. Together with the Warburg effect and the increased glutaminolysis, lipid metabolism has emerged as essential for tumor development and progression. Indeed, several investigations have demonstrated the consequences of lipid metabolism alterations in cell migration, invasion, and angiogenesis, three basic steps occurring during metastasis. In addition, obesity and associated metabolic alterations have been shown to augment the risk of cancer and to worsen its prognosis. Consequently, an extensive collection of tumorigenic steps has been shown to be modulated by lipid metabolism, not only affecting the growth of primary tumors, but also mediating progression and metastasis. Besides, key enzymes involved in lipid-metabolic pathways have been associated with cancer survival and have been proposed as prognosis biomarkers of cancer. In this review, we will analyze the impact of obesity and related tumor microenviroment alterations as modifiable risk factors in cancer, focusing on the lipid alterations co-occurring during tumorigenesis. The value of precision technologies and its application to target lipid metabolism in cancer will also be discussed. The degree to which lipid alterations, together with current therapies and intake of specific dietary components, affect risk of cancer is now under investigation, and innovative therapeutic or preventive applications must be explored.

Project description:PurposeCutaneous metastasis (CM) accounts for 5-30% of patients with breast cancer (BC) and presents unfavorable response to treatment and poor prognosis. A better understanding of the molecular alterations involved in metastasis is essential, which would help identify diagnostic and efficacy biomarkers for CM.MaterialsWe retrospectively reviewed a total of 13 patients with histological or cytological diagnosis of breast cancer and CM. Clinical information was extracted from the medical records. The mutational landscape of matched primary tumors with their lymph nodes or CM tissues were analyzed using next-generation sequencing (NGS) of 425 cancer-relevant genes. All tissues were also analyzed by immunohistochemistry (IHC). The association of prognosis with various clinical and molecular factors was also evaluated.ResultsMore than half of the patients were Ki67 low (< 50%, 53.7%). Most patients (12, 92.3%) had other metastasis sites other than skin. The median time from diagnosis to the presentation of CM (T1) was 15 months (range: 0-94 months) and the median time from CM to death (T2) was 13 months (range 1-78). The most frequently altered genes across the three types of tissues were TP53 (69.6%, 16/23), PIK3CA (34.8%, 8/23), and MYC (26.1%). The number of alterations in CM tends to be higher than in primary tumors (median 8 vs. 6, P = 0.077). Copy number loss in STK11, copy number gain in FGFR4, TERT, AR, FLT4 and VEGFA and mutations in ATRX, SRC, AMER1 and RAD51C were significantly enriched in CM (all P < 0.05). Ki67 high group (> 50%) showed significantly shorter T1 than the Ki67 low group (≤ 50%) (median 12.5 vs. 50.0 months, P = 0.036). TP53, PIK3CA mutations, and TERT amplification group were associated with inferior T2 (median 11 vs. 36 months, P = 0.065; 8 vs. 36 months, P = 0.013, 7 vs. 36 months, P = 0.003, respectively). All p values were not adjusted.ConclusionWe compared the genomic features of primary breast cancer tissues with their corresponding CM tissues and discussed potential genes and pathways that may contribute to the skin metastasis of advanced breast cancers patients. TP53, PIK3CA mutant, and TERT amplification may serve as biomarkers for poor prognosis for CM patients.

Dataset Information

Alterations of Ion Homeostasis in Cancer Metastasis: Implications for Treatment.

Publications

Alterations of Ion Homeostasis in Cancer Metastasis: Implications for Treatment.

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