TAMing pancreatic cancer: combat with a double edged sword

Abstract

Among all the deadly cancers, pancreatic cancer ranks seventh in mortality. The absence of any grave symptoms coupled with the unavailability of early prognostic and diagnostic markers make the disease incurable in most of the cases. This leads to a late diagnosis, where the disease would have aggravated and thus, incurable. Only around 20% of the cases present the early disease diagnosis. Surgical resection is the prime option available for curative local disease but in the case of advanced cancer, chemotherapy is the standard treatment modality although the patients end up with drug resistance and severe side effects. Desmoplasia plays a very important role in chemoresistance associated with pancreatic cancer and consists of a thick scar tissue around the tumor comprised of different cell populations. The interplay between this heterogenous population in the tumor microenvironment results in sustained tumor growth and metastasis. Accumulating evidences expose the crucial role played by the tumor-associated macrophages in pancreatic cancer and this review briefly presents the origin from their parent lineage and the importance in maintaining tumor hallmarks. Finally we have tried to address their role in imparting chemoresistance and the therapeutic interventions leading to reduced tumor burden.

Single-cell transcriptome analysis of tumor and stromal compartments of pancreatic ductal adenocarcinoma primary tumors and metastatic lesions

“…3 f) [ 28 ]. Since besides hematopoietic stem cells TAMs can also be derived from tissue-resident macrophages [ 29 ], the difference between the TAMs from liver metastatic lesions and the primary tumors observed in our study could be, in part, due to the intrinsic differences between liver-resident macrophages and pancreas-resident macrophages. Further studies are needed to verify this possibility.…”

E-Cadherin in Pancreatic Ductal Adenocarcinoma: A Multifaceted Actor during EMT

“…Different factors can concur in limiting T cell trafficking in the tumor bed and macrophages are one of them [153][154][155]. For example, it has been reported that extratumoral macrophages negatively regulate the infiltration of T lymphocytes into PDAC [156] but less is known about TAMs, one the most abundant leukocytes infiltrating pancreatic cancer [157]. Peranzoni et al observed that stromal macrophages hinder CD8 + T lymphocytes motility in lung cancer tumor microenvironment by cell-cell interaction [155].…”

“…As mentioned before, T cells can express α E (CD103)β 7 [131] that, upon engagement with E-cadherin on macrophages, may determine a slowdown of lymphocytes. Moreover, TAMs, usually polarized towards an immunosuppressive M2-phenotype [157], can exploit the reduced spatial proximity with T cells to better inhibit their activity. However, the functional significance of this interaction may not be always detrimental.…”

Cathepsin Inhibition Modulates Metabolism and Polarization of Tumor-Associated Macrophages

“…Myeloid cells differentiating into tumor-associated macrophages (TAM) represent a crucial immune cell population within the tumor stroma. Dense TAM infiltration of the tumor microenvironment is usually associated with poor prognosis and increased resistance to chemotherapy, primarily due to a multitude of TAM-derived secreted mediators known to facilitate invasiveness, tumor cell survival, and immune evasion [45][46][47]. These macrophage-derived effector molecules include secreted cathepsins, such as cathepsin B, L, and S, which are known to contribute to the degradation of extracellular matrix compounds.…”