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The pro-tumorigenic host response to cancer therapies

Abstract

Resistance to cancer therapy remains a major challenge in clinical oncology. Although the initial treatment phase is often successful, eventual resistance, characterized by tumour relapse or spread, is discouraging. The majority of studies devoted to investigating the basis of resistance have focused on tumour-related changes that contribute to therapy resistance and tumour aggressiveness. However, over the last decade, the diverse roles of various host cells in promoting therapy resistance have become more appreciated. A growing body of evidence demonstrates that cancer therapy can induce host-mediated local and systemic responses, many of which shift the delicate balance within the tumour microenvironment, ultimately facilitating or supporting tumour progression. In this Review, recent advances in understanding how the host response to different cancer therapies may promote therapy resistance are discussed, with a focus on therapy-induced immunological, angiogenic and metastatic effects. Also summarized is the potential of evaluating the host response to cancer therapy in an era of precision medicine in oncology.

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Fig. 1: Host-mediated immunological responses.
Fig. 2: Host-mediated angiogenic responses.
Fig. 3: Host-mediated metastatic responses.

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Acknowledgements

The author thanks the referees of this manuscript who provided excellent comments that substantially improved the Review. The author also thanks R. Kerbel, J. Condeelis and M. Oktay for their comments and suggestions throughout the writing process. It is with regret that not all relevant studies could be cited due to space limitation. This Review and many of the original studies published by the author on this specific subject have been supported by European Research Council (ERC) grants (current 771112).

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Correspondence to Yuval Shaked.

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The author is a co-founder of OncoHost, a biotechnology company that utilizes the host response profile in the clinical setting in order to improve anticancer therapies. The author is listed on several patents related to host responses to anticancer drugs.

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Nature Reviews Cancer thanks M. De Palma and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Tumour-associated macrophages

(TAMs). A heterogeneous population of differentiated monocytes found in the microenvironment of solid tumours, mainly consisting of cells with immunosuppressive functions (also known as M2-like macrophages) as well as a minor population of cells with pro-inflammatory functions (also known as M1-like macrophages).

ATP-binding cassette (ABC) transporters

Transporter proteins composed of transmembrane and ATPase protein subunits that take up or export various substrates across the cell membrane. In cancer cells, they contribute to therapy resistance via their ability to expel drugs from the cell.

Tubulin-binding agents

A family of anti-neoplastic chemotherapeutic drugs that interfere with the depolarization or polymerization of microtubules required for cell mitosis. As the rapidly proliferating malignant cells cannot divide in the presence of tubulin-binding agents, they eventually undergo apoptosis.

Alkylating agents

A family of anti-neoplastic chemotherapeutic drugs that act to replace hydrogen with an alkyl group in the replicated DNA during cell proliferation. The alkyl group is attached to the guanine base of the DNA, thus causing DNA damage and, ultimately, cell apoptosis.

Anti-metabolite agents

A family of anti-neoplastic chemotherapeutic drugs that interfere with the metabolic pathway of DNA replication in S phase, ultimately inducing cell apoptosis. Among these agents are folic acid antagonists, and purine and pyrimidine anti-metabolites.

Myeloid cells

Leukocytes from the haematopoietic myeloid lineage. These are usually premature cells that differentiate into monocytes, macrophages, neutrophils, basophils, eosinophils, erythrocytes and megakaryocytes.

Extracellular vesicles

(EVs). Lipid bilayer particles that contain DNA, RNA and proteins and that are released from the cell surface membrane. They vary in size (usually between 50 and 500 µm) and are categorized as exosomes, microparticles and apoptotic bodies.

Thymus-associated endothelial cells

Endothelial cells residing in the thymus that contribute to the regeneration of thymus tissue following radiation.

Bronchoalveolar lavage

An invasive medical procedure involving the instillation of saline solution into a subsegment of the lung area. The liquid is then retrieved by suction and analysed for cells, protein content and foreign materials.

Amphiregulin

A ligand of the epidermal growth factor receptor (EGFR) expressed by epithelial cells. Its signalling through EGFR contributes to the development and growth of normal epithelial cells. In cancer, it promotes tumour cell proliferation.

Epiregulin

A ligand of the epidermal growth factor receptor that contributes to inflammation, wound healing and tissue repair.

Lymphangiogenesis

The formation of new lymphatic vessels from pre-existing lymphatic vessels, in a process similar to angiogenesis. In cancer, lymphangiogenesis is associated with metastasis.

Vascular-disrupting agents

(VDAs). A family of drugs with potent tumour vessel disruption ability. These cytotoxic-like agents (usually tubulin-binding or tubulin-destabilizing agents) rapidly promote cancer vessel collapse leading to necrosis.

Haemangiocytes

Bone marrow-derived pro-angiogenic haematopoietic cells that were shown to contribute to tumour angiogenesis. They are usually localized in the perivascular zone of the growing blood vessel and contribute to its integrity.

Vasculogenesis

The process of systemic formation of blood vessels. As opposed to angiogenesis, which is a local process of blood vessel formation from pre-existing vessels, vasculogenesis is mediated by systemic mobilization of bone marrow-derived pro-angiogenic cells, such as endothelial precursor cells, which incorporate to generate blood vessels.

Fibrosis

The formation or thickening of connective tissue in response to injury or chronic inflammation.

Laparoscopy

A procedure in which a fibre-optic device is usually inserted into the abdomen in order to fulfil a surgical procedure. It is sometimes used instead of open surgery to minimize recovery time.

Tumour microenvironment of metastasis

(TMEM). An anatomical structure within solid tumours composed of a cancer cell and a perivascularly located macrophage expressing TIE2 and vascular endothelial growth factor (VEGF). When both of these cells tightly bind to a blood vessel endothelial cell, the secretion of local VEGF contributes to blood vessel permeability, opening a doorway through which tumour cells can extravasate and disseminate from the primary tumour site.

Pre-metastatic niche

A physical area in a secondary non-malignant site that provides a favourable environment for circulating tumour cells to seed and proliferate in order to establish a metastatic lesion.

Resolvins

Polyunsaturated fatty acid metabolites that, in response to injury and subsequent inflammation, resolve inflammation and help restore tissue homeostasis.

Desmoplastic tumours

Tumours containing a large amount of dense connective and fibrous tissue, such as pancreatic ductal adenocarcinoma.

Erythroleukaemia

A relatively rare haematological malignancy, classed as a subtype of acute myeloid leukaemia arising from malignant erythroid blasts. Owing to the lack of differentiated erythroid cells, the disease is characterized by anaemia, thrombocytopenia and leukopenia.

Epoxide hydrolase

A class of enzymes that metabolize epoxide residues into hydroxyls. There are several enzymes in this family, distinguished from each other by their preferred substrates. They are known to detoxify genotoxic compounds and play a role in physiological signalling.

Abscopal effect

A rare phenomenon in which local radiation causes tumour shrinkage not only at the irradiated tumour site but also at distant tumour sites (usually metastatic lesions) located outside the field of irradiation.

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Shaked, Y. The pro-tumorigenic host response to cancer therapies. Nat Rev Cancer 19, 667–685 (2019). https://doi.org/10.1038/s41568-019-0209-6

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