The Importance of the Tumor Microenvironment and Hypoxia in Delivering a Precision Medicine Approach to Veterinary Oncology

Abstract

Treating individual patients on the basis of specific factors, such as biomarkers, molecular signatures, phenotypes, environment, and lifestyle is what differentiates the precision medicine initiative from standard treatment regimens. Although precision medicine can be applied to almost any branch of medicine, it is perhaps most easily applied to the field of oncology. Cancer is a heterogeneous disease, meaning that even though patients may be histologically diagnosed with the same cancer type, their tumors may have different molecular characteristics, genetic mutations or tumor microenvironments that can influence prognosis or treatment response. In this review, we describe what methods are currently available to clinicians that allow them to monitor key tumor microenvironmental parameters in a way that could be used to achieve precision medicine for cancer patients. We further describe exciting novel research involving the use of implantable medical devices for precision medicine, including those developed for mapping tumor microenvironment parameters (e.g., O 2 , pH, and cancer biomarkers), delivering local drug treatments, assessing treatment responses, and monitoring for recurrence and metastasis. Although these research studies have predominantly focused on and were tailored to humans, the results and concepts are equally applicable to veterinary patients. While veterinary clinical studies that have adopted a precision medicine approach are still in their infancy, there have been some exciting success stories. These have included the development of a receptor tyrosine kinase inhibitor for canine mast cell tumors and the production of a PCR assay to monitor the chemotherapeutic response of canine high-grade B-cell lymphomas. Although precision medicine is an exciting area of research, it currently has failed to gain significant translation into human and veterinary healthcare practices. In order to begin to address this issue, there is increasing awareness that cross-disciplinary approaches involving human and veterinary clinicians, engineers and chemists may be needed to help advance precision medicine toward its full integration into human and veterinary clinical practices.

A Comparative View on Molecular Alterations and Potential Therapeutic Strategies for Canine Oral Melanoma

“…However, despite the preclinical utility of in vitro cell cultures, they do not recapitulate the complex network of tumour-associated cells and secreted molecules that constitute the tumour microenvironment in vivo. In this way, tumour cells are not subject to the bidirectional communication with stromal and immune cells [43], and cells are cultured in normoxyic incubators that do not reflect hypoxic selection pressure within solid tumours [21]. Similarly, xenograft models with subcutaneous transplantation of tumours into rodent models enable preclinical study of drug toxicity, but recipients are necessarily immune deficient, and thus tumour growth is not in the context of the immune microenvironment.…”

“…An essential element to consider in the tumour microenvironment is that of tumour hypoxia, with varying oxygen tensions present in different regions of the tumour, and creating a selection pressure for cells that can switch to a hypoxic phenotype through upregulation of hypoxia-inducible factors [21]. This also includes upregulation of a subset of hypoxia regulated miRNAs (HRMs), such as miRNA-450, miRNA-301, and miRNA-146 [89].…”

“…COM remains a challenging disease in veterinary medicine, complicated by both interpatient and intratumour heterogeneity, giving rise to varied responses to conventional therapy and rapid selection of resistant tumour clones [5]. Precision medicine is now at the forefront of human oncology, whereby treatment is selected to achieve maximum benefit for the patient, while minimising the personal and financial costs associated with ineffective treatments [21]. This concept is equally desirable for our veterinary patients, aiming for targeted therapies to disrupt dysregulated pathways that are unique to cancer cell biology, thereby reducing systemic side effects [36].…”

“…The aim of this review is to present our current understanding of the molecular alterations that underlie COM. This is a highly heterogenous disease, thus two patients may have the same histological diagnosis while having different underlying molecular changes [21]. As such, it is useful to take a broader view to determine the overarching cellular pathways and functions that are critically deregulated during oncogenesis.…”

The Role of the Hypoxia-Related Unfolded Protein Response (UPR) in the Tumor Microenvironment

“…HIF-1 and HIF-2 promote increases in the lymphangiogenic and angiogenic responses as well as metabolic changes that lead to a shift to glycolysis [5][6][7][8][9][10][11][12][13][14]. While these transcriptional changes enhance the tumor growth and viability, they also offer potential targets for new cancer therapeutic strategies [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29].…”