Tumour

Tumours (neoplasm) are groups of abnormally growing cells, which can be benign (non-cancerous) or malignant (cancerous). Benign tumours grow slowly and do not spread elsewhere. Pre-malignant cells (hyperplasia, atypia, metaplasia, dysplasia) may develop into cancer if not treated. Malignant neoplasm (cancer) grows in an uncontrolled way into nearby tissues and can spread to distant locations (metastasise). Bone marrow, lungs, and liver are the most common sites of metastases.

Fibroblasts synthesize and deposit extracellular matrix (ECM) proteins, which can constitute a major fraction of tumour mass. Vascular network and microcirculation in tumour is disorganized, with nonvascularized areas, arteriovenous anastomoses (shunts), discontinuous capillaries (sinusoids), leaky blood "vessels" without endothelium, and dysfunctional regulation of blood flow. Vasculature is normally supported by tubulin and actin, but only by tubulin in solid tumours. Blood in tumour vasculature may be more viscous than normally because of released ECM proteins. Capillary diameter may be two times larger than in normal tissue. Inadequate blood flow leads to low availability of oxygen and prevalence of hypoxic ([pO2] ≤ 2.5 mmHg) volumes inside the tumour. The efficacy of radiotherapy and most chemotherapies is reduced in hypoxic regions. Acute hypoxia (< 2 h) is caused by temporary reduction of red blood cell flux in tumour microvessels (hypoxemic hypoxia) or blood flow (ischemic hypoxia). Chronic hypoxia (> 2 h) is caused by increased distances between vessels. In hypoxemic hypoxia only the oxygen supply is reduced while the supply of other nutrients and waste removal is preserved. The wound healing and angiogenesis machineries of endothelial cells, tumour-associated macrophages (TAMs), and platelets support the survival of cancer cells and metastasis. Treatments targeting tumour vasculature have been developed and are under active research (Prokopiou et al., 2013).

The glucose metabolism in tumours is directed toward glycolysis leading to formation of lactic acid, not only because the availability of oxygen may be reduced, but also in normoxic tumour regions (aerobic glycolysis, Warburg effect). Glucose uptake is upregulated also to produce ribose for nucleotide synthesis via pentose phosphate pathway (Icard and Lincet, 2012). Citrate is directed from TCA cycle to cytosolic anabolic processes by upregulation of citrate carrier (CIC) which transports citrate from mitochondria into cytosol. Glutamine is the second most abundant nutrient in the blood after glucose, and oncogenic mutations and epigenetic adaptations allow tumour cells to increase glutaminolysis to sustain their growth (Zhu et al., 2017).

Interstitial pressure tends to be elevated towards the centre of tumour. This affects the kinetics of large molecules such as monoclonal antibodies, used in radioimmunotherapy and imaging, since convection is a major driving force for tissue distribution of macromolecules (Baxter & Jain, 1989 and 1990; Jain, 1990). On the other hand, leaky vasculature and defective lymphatic drainage causes the enhanced permeability and retention (EPR) effect, where the uptake of labelled albumin and other macromolecules is increased. EPR effect can be exploited in tumour imaging and therapeutics (Maeda et al., 2000).

Activated T lymphocytes and NK cells express immune checkpoint receptors which play a key role in maintaining physiologic self-tolerance, but these pathways are used by cancer cells to evade immune surveillance. Immune checkpoint inhibitor (ICI) therapy (including anti-PD-1, anti-CTLA-4, and anti-CD38 drugs) targets this tumour survival strategy. However, tumours can upregulate other inhibitory receptors such as LAG3, TIGIT, and TIM3 (Sharma et al., 2017; Gide et al., 2018; Liu et al., 2021).

The heterogeneity of the microenvironment of tumour cells affects the response to cancer therapy. While biopsy samples represent only a fraction of the tumour, PET/CT and PET/MR imaging allow to measure the metabolic heterogeneity of the whole tumour, although with less detail and with certain methodological challenges (Zhao et al., 2005; van Baardwijk et al., 2008; Asselin et al., 2012; Orlhac et al., 2014; Orlhac et al., 2017).

Functional imaging

Increased glucose uptake in tumours is commonly quantified or semi-quantified using [18F]FDG. If arterial or arterialized venous plasma input function is available, then either Ki or related FUR can be calculated. Glucose concentration in plasma should then be measured, too, to convert Ki or FUR to metabolic rate of glucose; however, that is not a precise estimate, since lumped constant for tumours is variable, probably even inside one tumour. Without plasma data only semi-quantitative assessments can be made, including SUV, dual-time point imaging, and tumour-to-normal tissue ratio (T/N). Liver or muscle are often used as the reference tissue, although muscle [18F]FDG uptake is known to be highly variable, and results are dependent on the definition of the liver or muscle ROI. [18F]FDG is not well suitable for imaging all tumours: neuroendocrine and prostate tumours often have low [18F]FDG uptake, while in the brain the [18F]FDG uptake is high also in the normal tissue.

Many cancer have upregulated amino acid transport and protein synthesis rate. Amino-acid uptake is quantified using labelled amino-acids and amino-acid derivatives, including [11C]methionine, [18F]fluoroethyltyrosine (FET), glutamine analogues, [18F]FDOPA, and leucine derivative [18F]FACBC (fluciclovine) (Elschot et al., 2017; Jambor et al., 2017). Amino acids can be used as boron-10 carriers for BNCT.

Sarcomas and lymphomas tend to have higher perfusion than carcinomas, and larger tumours lower perfusion than smaller tumours. Perfusion in tumours can be measured using [15O]H2O, or using the initial uptake phase of several PET radiopharmaceuticals, including that of [18F]FDG (Mullani et al., 2008). Wadsworth et al. (2017) used 2-[18F]-fluoroethanol to measure perfusion in mouse tumour models. Tumours with increased perfusion and oxidative metabolism can be detected using [11C]acetate (Schiepers et al., 2008; Seppälä et al., 2009; Jambor et al., 2010; Strandberg et al., 2014).

High-grade tumours typically have necrotic and hypoxic regions. PET radiopharmaceuticals targeting hypoxia are widely used, and also imaging of apoptosis and cell death is becoming feasible.

[11C]choline and [18F]choline and its derivatives can be used as markers for cellular proliferation, because choline is a precursor for the biosynthesis of membrane phospholipids (Hara et al., 1997; Sutinen et al., 2004; Evangelista et al., 2015).

Cell proliferation requires DNA synthesis, and therefore radiolabelled nucleosides, such as thymidine analogue [18F]FLT can be used for tumour imaging.

Arginase is typically overexpressed in tumour cells, but also in inflammatory conditions.

Folate receptors are often overexpressed on cancer cells, offering a target for imaging and therapy (Müller & Schibli, 2011; Müller, 2013).

Copper transporter 1 (CTR1) is overexpressed in many cancer types, and [64Cu]CuCl2 can have a role in detecting tumours and for example in staging of prostate cancer (Capasso et al., 2015).

Gene c-MYC, involved in oncogenesis, encodes transcription factor c-Myc, which activates numerous target genes, including gene for transferrin receptor 1. Transferrin receptors are often overexpressed in tumour cells because of increased demand for iron, and for example 68Ga3+-labelled transferrin can be used for detecting MYC-positive and other cancers.

Active cancer-associated fibroblasts can be targeted in imaging and theranostics. These include FAP inhibitors such as [68Ga]FAPI. Tumour-to-background ratio is better with [68Ga]FAPI than with [18F]FDG in organs where physiological [18F]FDG uptake is high (Giesel et al., 2021).

Urokinase plasminogen activator receptor (uPAR) is located on the cell surface, interacting with urokinase plasminogen activator (uPA), integrins, and other proteins. It can promote cell proliferation, motility, proteolysis, and angiogenesis, and its expression is upregulated in cancer (Mahmood et al., 2018; Ahn et al., 2019). The expression of uPAR can be assessed in vivo with [68Ga]Ga-NOTA-AE105 PET (Skovgaard et al., 2017; Carlsen et al., 2022).

Tumour phenotype can change during disease progression, leading to variable expression of receptors on cancer cells. Heterodimeric and bispecific radioligands could be used to enhance the detection of tumours (Judmann et al., 2020). For instance, radiopeptides targeting both PSMA and GRPR have been developed (Rivera-Bravo et al., 2021).

Inflammation

Tumours are usually accompanied with inflammation, and the uptake of many PET radiopharmaceuticals is increased in inflammation. TSPO tracers may be useful in detecting inflammation in tumours, since uptake of TSPO ligands is generally not increased in tumours (Wu et al., 2014). However, TSPO is upregulated in some cancer cell lines and tumour specimens. In gliomas, high TSPO signal in solid core regions may be caused by tumour cells, while lower signal in the tumour rim is caused by immune cells (Weidner et al., 2023). TSPO imaging in gliomas is reviewed by Zinnhardt et al (2021).

COX-1 and COX-2 specific PET radiopharmaceuticals have been developed for inflammation imaging, but could be repurposed for oncology (Boyle et al., 2021 and 2022).

Cell-based treatment strategies utilize for example T cells, and the homing of transplanted cells can be studied by in vitro labelling of the cells. [18F]FDG has been traditionally used for cell labelling, but labelling with hexadecyl-4-[18F]fluorobenzoate ([18F]HFB) may provide more accurate results of the distribution of the transplanted cells (Ma et al., 2005; Zhang et al., 2012).

The drugs used for immune checkpoint blocking, such as anti-PD-1 agents, have been used in immuno-PET. Daratumumab is an antibody targeting CD38, and it has been labelled with 89Zr (Ehlerding et al., 2017), and also a 68Ga-labelled CD38-specific nanobody has been developed (Wang et al., 2021). 89Zr-labelled TIGIT-specific probe could be used to select patients for anti-TIGIT therapy (Shaffer et al., 2021).

TNM classification

Union Internationale Contre le Cancer (UICC) and American Joint Committee on Cancer have published and updated TNM classification of malignant tumours, which is widely used standard for cancer staging. UICC TNM classification is an anatomically-based system with three categories: T category describes the primary tumour site, N category describes regional lymph node involvement, and M category describes the metastatic spread.

Eiber et al (2018) have proposed a molecular imaging TNM system (miTNM) as a standardized reporting framework for PSMA-ligand PET/CT and PET/MRI in prostate cancer.

Werner et al (2018) have proposed a molecular imaging reporting and data systems (MI-RADS) framework for targeted radiotracers with theranostic implications. Their work included RADS classifications for PSMA- and SSTR-targeted PET imaging.


See also:


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Updated at: 2023-09-15
Created at: 2016-03-18
Written by: Vesa Oikonen