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Are certain cells within tumors really good or bad? Aren’t cells just cells, neither good nor bad? Engendering a distorted view of biology, conceptual landscapes that assign cells such non-scientific labels commit them to unnatural pre-ordained, immutable fates. Obscuring rather than illuminating, such cartoon landscapes are populated by static dummy stand-ins that bear little or no resemblance to their real counterparts, which are actually much more dynamic. Such labels also restrict consideration of what and how to examine and why.

Thus, rather than ask whether a tumor-associated cell is good or bad, examining the role of each cell type over the course of tumor progression and comparing a given cell type across tumors is more fruitful. Doing so reveals that most non-cancerous cell types within cancers are capable of both promoting and inhibiting tumor growth. Examining tumor-dwelling cells in this fashion is more fruitful because it helps alter the approach from the scorched earth one that sees them as either inherently ‘good’ or ‘bad’ to one that considers them amenable to manipulations, i.e., future therapies, that could alter their fates to inhibit tumor growth.

Apart from cancer cells themselves, solid tumors usually contain CAFs (cancer-associated fibroblasts), MDSC (Myeloid-derived suppressor cell – Wikipedia), TAMs (Tumor-associated macrophage – Wikipedia), TANs (Tumor-Associated Neutrophils), TILs (Tumor-infiltrating lymphocytes – Wikipedia), and blood vessel-associated cells.

This answer shares brief summaries of some of these various tumor-associated cells, highlighting the inherent ambiguity in determining what they augur for various cancer outcomes.

CAFs (Cancer-Associated Fibroblasts)

Key cells in wound healing, that fibroblasts from different tissues are quite different is itself a fairly recent realization (1).

CAF OTOH usually differ from their normal counterparts through increased rate of proliferation, and altered expression of extracellular matrix (ECM) and growth factors (2).

CAF are hypothesized to remodel the ECM in tumor tissue and provide tumor cells with growth factors (3).

While there are plenty of in vitro and mouse model (4, 5, 6) and even human (7) studies with data suggesting CAF promote tumor growth and invasion, at least one in vitro and mouse model study (8) also showed that high levels of estrogen receptor alpha- expressing CAF inhibited infiltration of TAM, an outcome that in turn suppressed prostate cancer invasion.

TAMs (Tumor-associated macrophage – Wikipedia)

Meta-analyses (9, 10) of TAM studies in most human solid tumors conclude they could be either pro- or anti-tumorigenic, specifically that their presence is associated with worse overall survival in gastric, urogenital, and head and neck cancer, and better overall survival in colorectal cancer.

TANs (Tumor-Associated Neutrophils)

TANs epitomize the Janus – Wikipedia face of non-cancerous tumor-associated cells (11). At least one mouse model study (12) chose to examine TAN phenotype and effects at different points of time during tumor progression in mouse lung and mesothelioma models. Doing so showed TANS are tumor-killing (cytotoxic) in early tumors but tumorigenic in established tumors. Such an answer wouldn’t be possible if researchers pursued their studies stuck on the notion that TANs are inherently ‘bad’, i.e., tumor-promoting.

Obviously such tumor progression studies are far less feasible in humans. Instead TAN snapshots of well-established human tumors suggest they’re associated with poor prognosis in renal cell carcinoma, melanoma, colorectal cancer, and many others (13). Of course, this still leaves their role in human tumor initiation open-ended.

TILs (Tumor-infiltrating lymphocytes – Wikipedia)

For the most part, heavy tumor infiltration by CD8+ CTLs (Cytotoxic T cell – Wikipedia) (14) augurs well for cancer patients except in the case of renal cell carcinoma (15).

Situation is even more confusing and ambiguous with prognoses ranging from poor to no effect to good across T helper cell – Wikipedia phenotypes and tumor types (14). Prevailing norm of forcing CD4 T cells into artificial bins/buckets of phenotypes such as Th1, Th2, Th17, Treg, etc., is a major source of such confusion (16), classic example of missing the forest for the trees.

Bibliography

1. Rinn, John L., et al. “Anatomic demarcation by positional variation in fibroblast gene expression programs.” PLoS Genet 2.7 (2006): e119. http://journals.plos.org/plosgen…

2. Kalluri, Raghu, and Michael Zeisberg. “Fibroblasts in cancer.” Nature Reviews Cancer 6.5 (2006): 392-401. http://s3.amazonaws.com/academia…

3. Bhowmick, Neil A., Eric G. Neilson, and Harold L. Moses. “Stromal fibroblasts in cancer initiation and progression.” Nature 432.7015 (2004): 332-337. https://www.ncbi.nlm.nih.gov/pmc…

4. Franco, Omar E., et al. “Cancer associated fibroblasts in cancer pathogenesis.” Seminars in cell & developmental biology. Vol. 21. No. 1. Academic Press, 2010. https://www.researchgate.net/pro…

5. Chiarugi, Paola. “Cancer-associated fibroblasts and macrophages: Friendly conspirators for malignancy.” Oncoimmunology 2.9 (2013): e25563. http://www.tandfonline.com/doi/p…

6. Shiga, Kazuyoshi, et al. “Cancer-associated fibroblasts: their characteristics and their roles in tumor growth.” Cancers 7.4 (2015): 2443-2458. http://www.mdpi.com/2072-6694/7/…

7. Erez, Neta, et al. “Cancer associated fibroblasts express pro-inflammatory factors in human breast and ovarian tumors.” Biochemical and biophysical research communications 437.3 (2013): 397-402.

8. Yeh, Chiuan-Ren, et al. “Estrogen receptor α in cancer associated fibroblasts suppresses prostate cancer invasion via reducing CCL5, IL6 and macrophage infiltration in the tumor microenvironment.” Molecular cancer 15.1 (2016): 7. https://pdfs.semanticscholar.org…

9. Zhang, Qiong-wen, et al. “Prognostic significance of tumor-associated macrophages in solid tumor: a meta-analysis of the literature.” PloS one 7.12 (2012): e50946. http://journals.plos.org/plosone…

10. Kim, Jaehong, and Jong-Sup Bae. “Tumor-associated macrophages and neutrophils in tumor microenvironment.” Mediators of inflammation 2016 (2016). http://downloads.hindawi.com/jou…

11. Gregory, Alyssa D., and A. McGarry Houghton. “Tumor-associated neutrophils: new targets for cancer therapy.” Cancer research 71.7 (2011): 2411-2416. http://cancerres.aacrjournals.or…

12. Mishalian, Inbal, et al. “Tumor-associated neutrophils (TAN) develop pro-tumorigenic properties during tumor progression.” Cancer Immunology, Immunotherapy 62.11 (2013): 1745-1756.

13. Donskov, Frede. “Immunomonitoring and prognostic relevance of neutrophils in clinical trials.” Seminars in cancer biology. Vol. 23. No. 3. Academic Press, 2013. https://www.researchgate.net/pro…

14. Fridman, Wolf Herman, et al. “The immune contexture in human tumours: impact on clinical outcome.” Nature Reviews Cancer 12.4 (2012): 298-306. https://www.researchgate.net/pro…

15. Nakano, Osamu, et al. “Proliferative activity of intratumoral CD8+ T-lymphocytes as a prognostic factor in human renal cell carcinoma.” Cancer research 61.13 (2001): 5132-5136. http://cancerres.aacrjournals.or…

16. Tirumalai Kamala’s answer to What’s the difference between Th1 and Th2 helper T-cell subsets?

https://www.quora.com/Besides-cancer-cells-how-many-cell-types-are-there-in-tumors-What-are-the-good-cells-and-bad-cells/answer/Tirumalai-Kamala

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