Chapter Two - Predictive value of collagen in cancer
Introduction
Cancer is a complex disease and remains a significant cause of mortality worldwide in spite of extensive work towards personalized diagnosis and treatment (Sung et al., 2021). Understanding the molecular contributions within the complex tumor microenvironment that result in progression and poor prognosis is a defining area that requires ongoing investigation with current technologies. Within the tumor microenvironment, collagen plays a significant role in pathological progression, outcomes, and therapeutic response (Martins Cavaco, Dâmaso, Casimiro, & Costa, 2020; Valkenburg, de Groot, & Pienta, 2018; Xu et al., 2019; Yamauchi, Barker, Gibbons, & Kurie, 2018). Collagen proteins are the main component of stroma matrix and are known facilitators of cancer progression and metastasis (Fang, Yuan, Peng, & Li, 2014; Winkler, Abisoye-Ogunniyan, Metcalf, & Werb, 2020; Xu et al., 2019). These stroma proteins are the least understood in terms of translational and post-translational structural regulation. There are 28 different types of collagen proteins classified by suprastructural type. Each collagen type has a common structural feature triple helical region composed of three polypeptide chains enriched for G-X-Y composition, where X and Y can vary between proline or 4-hydroxyproline (Ricard-Blum, 2011; Shoulders & Raines, 2009). Diversity of the collagen superfamily increases at the translational level by the presence of isoforms, hybrid isoform chains, single point mutations, splice variants, and post-translational modifications that cross-link to other proteins (Myllyharju & Kivirikko, 2004; Ricard-Blum, 2011; Shoulders & Raines, 2009).
Collagen fiber regulation takes place uniquely outside of the cell and is controlled through an assortment of other extracellular matrix stroma proteins and enzymes that regulate fiber packing, extension, and thickness (Bonnans, Chou, & Werb, 2014; Myllyharju & Kivirikko, 2004). Structural collagen changes influence cell signaling, adhesion, proliferation, migration, metastasis and immune recruitment (Hohenester, Sasaki, Giudici, Farndale, & Bächinger, 2008; Tichet et al., 2015). Multiple cell types including fibroblasts, cartilage cells, keratinocytes, macrophages, T cells, and lymphocytes produce their own collagen niches (Chanmee, Ontong, Konno, & Itano, 2014; Choi, Byun, Kwon, & Park, 2015; Handley, Bateman, Oakes, & Lowther, 1975; Nissen, Karsdal, & Willumsen, 2019; Zhang & Zhang, 2020). These niches produce localized gradients through which small molecules, growth factors, and other signaling factors influence nearby cells. In cancer, collagen restructuring has produced pathological hallmarks of cancer progression that include fiber organization around the tumor, deposition within the tumor or around the tumor, matrix stiffening, proteolytic products, immune recruitment, and cell phenotype. In this review, we summarize published accounts on the pathological contribution of stroma in cancer types that have high mortality worldwide. The predictive value of collagen as a readout for cancer progression, outcomes, and recurrence is outlined. Table 1 compiles recent publications on various genomic, proteomic, and microscopy assays that have been primarily used in clinical cohorts to evaluate the predictive value of collagen and stroma over the course of cancer. A perspective is presented summarizing knowledge gaps in collagen molecular features and noninvasive predictive testing that may be leveraged by new advances in technology.
Section snippets
Breast cancer
Female breast cancer is now the most commonly diagnosed cancer worldwide and the leading cause of death for women, with an estimated 2.3 million new cases worldwide in 2020 (Sung et al., 2021). Breast cancer risk is tightly linked to conversion from adipocyte tissue to increasing stroma composition (Boyd et al., 2002). Mammographic density in combination with breast cancer risk models increases accuracy in prediction of lifetime breast cancer risk (Brentnall et al., 2015; Winkel et al., 2017).
Lung cancer
Worldwide, lung cancer is the second most diagnosed cancer and has the highest mortality rate. Over 2.2 million individuals were diagnosed with lung cancer in 2020 and over 1.7 million died in the same year (Sung et al., 2021). Lung cancer is the number one diagnosed cancer in men with an incidence of 39/100,000 worldwide and leads male cancer mortality at 31.6/100,000 in developed countries. Globally, lung cancer is the third most frequently occurring cancer in women and second cause of female
Hepatocellular carcinoma (liver cancer)
From first world to third world countries, hepatocellular carcinoma (HCC) is a global epidemic affecting an estimated 10 million people worldwide with more than 800,000 people diagnosed each year (Siegel, Miller, & Jemal, 2020; Yang et al., 2019). HCC accounts for > 80% of primary liver cancers and is the fourth most common cancer-related death (El-Serag & Rudolph, 2007; Fitzmaurice et al., 2017). HCC is the fifth most common cancer in men worldwide and the seventh most common cancer in women (
Colon cancer
Colon cancer is the third most common cancer in men and second most common cancer in women. Worldwide, around 1.2 million new cases emerge per year (Sung et al., 2021). The 5-year survival rates for metastatic colon cancer has been reported as 12.3% in the United States, contrasting with a 91.4% 5-year survival rate if diagnosed in early stages (Siegel, DeSantis, & Jemal, 2014). Colon cancer occurs as an invasion of tumor cells into the submucosa to form a polyp, further into the muscularis
Pancreatic cancer
In 2020, pancreatic cancer was the 7th leading cause of cancer death in the world, yet retains one of the highest mortality rates. Pancreatic cancer accounts for almost as many deaths (466,000) as cases (496,000) due to poor prognosis (Sung et al., 2021). In 28 European countries, pancreatic cancer is expected to become the third leading cause of cancer death by 2025 as breast cancer deaths decline (Ferlay, Partensky, & Bray, 2016). Men have a slightly higher age standardized incidence and
Perspectives and conclusions
In cancer, collagen and other stroma influences all aspects of emergence, progression, metastasis, recurrence, and survival. The current literature survey has shown that collagen and stroma components have a strong predictive value. A noticeable aspect was that most studies that included predictive results did not cover details of the collagen structure. For instance, post-translational modifications have a significant role in influencing collagen structure in organization and access for
Acknowledgments
P.M.A. is supported by NIH/NCI R01CA253460; S.C.Z. is grateful for support from NIH/NCI T32CA193201.
Author contributions
P.M.A. initiated the topic and wrote the majority of the manuscript. S.C.Z. wrote specific segments and provided an overall editorial review of the manuscript.
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