With increasing evidence that acquired tumor resistance to cytotoxic therapies and intratumoral pathway–targeting agents is frequently inevitable, more research effort is being devoted to targeting the tumor microenvironment — the cancer’s “habitat.”
“Very often during chemotherapy and radiotherapy the cancer cells that survive in the tumor are the ones that resist the therapy either through existing mutations or new mutations,” explained David Brindley, PhD, DSc, professor of biochemistry at the University of Alberta in Edmonton, Canada. “Targeting the tumor microenvironment, including fat tissue in breast cancer, should produce effects that are independent of mutations in the tumor.”
Inflammatory and proinflammatory microenvironments are known to be tumorigenic.1 This includes adipose tissue, which releases inflammatory cytokines and can itself become inflamed in obesity. Tumors, in turn, can provoke or exacerbate tissue inflammation. Tumor-derived inflammatory cytokines increase lysophosphatidate (LPA) production through an enzyme in adipose tissue called autotaxin, which in turn increases cyclooxygenase 2 (COX-2) and furthers inflammatory cytokine production, Dr Brindley explained.
Inflammation promotes the growth and metastasis of tumors, as well as resistance to treatment, Dr Brindley told Cancer Therapy Advisor. Chronic inflammation also facilitates tumor immune evasion.
If researchers can disrupt this loop, they might be able to slow tumor progression and metastasis, improving the efficacy of existing therapies. Dr Brindley and his colleagues are helping to pioneer the preclinical study of LPA’s role in cancer microenvironments and tumor progression.1-3
Adipose tissue produces much of the body’s autotaxin, the enzyme that produces LPA, Dr Brindley said. When mice are fed a high-fat diet representative of the typical human diet, their fat tissue produces more autotaxin.
Inflamed adipose tissue is pathogenic. It is associated with insulin resistance, diabetes, dyslipidemia, hypertension, and atherosclerosis, Dr Brindley said. The “inflammatory milieu” also promotes breast tumor growth and metastasis, contributing to poor treatment outcomes. LPA produced by platelets appears to improve survival among circulating cancer cells and promotes metastatic bone tumors, for example.1,4
“Obesity is associated with an estimated 30% of breast cancers,” he said. “We propose that increased inflammation in breast adipose tissue is accompanied by increased autotaxin production and increased LPA signaling.”