Mazen Saeed

Pharmacology departm

ent

Ege univrsity

Monocytes

In Human

Cancer

Monocytes are part of the myeloid family, a group of hematopoietic derived cells.

David M. Richards et al.2012

Monocytes-macrophages play an active role in cancer development. (Pollard JW: Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer 2004, 4(1):71–78.)

In the steady-state ,Tissue development and maintenance of homeostasisDavid M. Richards et al.2012

Under inflammatory conditions, Supporting innate and adaptive immune responsesDavid M. Richards et al.2012

In presence of tumors ,Promoting all aspects of tumor initiation, growth, and development. Am J Transl Res. 2012; 4(4): 376–389. Published online Oct 10, 2012. PMCID: PMC3493031Jon G Quatromoni and Evgeniy Eruslanov

Function of monocytes

Origins of monocytes and macrophages

-In the steady-state, monocyte-derived macrophages (Mo-MΦ) and DCs (Mo-DCs).

-Under inflammatory conditions, inflammatory macrophages and monocyte-derived DCs.

-In presence of tumors, tumor-associated macrophages (TAMs) and monocytic MDSCs (M-MDSCs) David M. Richards et al.2012

Monocytes-Macrophages are the dominant leukocyte population found in the tumor microenvironment. (Biswas and Mantovani, 2010).

They represent up to 50% of the tumor mass, certainly operate as fundamental actors. Solinas et al 2009. Tumor-

associated macrophages (TAM) as major players of the cancer-related inflammation

M-MQ can be divided into two main classes

M1 macrophages (classically activated cells) 

M2 (alternatively activated) or TAM A. Mantovani et al

November 2009Journal of Leukocyte Biologyvol. 86 no. 5 1065-1073

M1 macrophages (classically activated cells)

n

Tumor-associated macrophages (TAMs) or M2

Tumor-associated macrophages (TAMs) or M2

key contributors to cancer-related inflammation Mantovani A, Sica A. Macrophages, innate immunity and cancer: balance, tolerance, and diversity. Curr Opin Immunol. 2010;22:231–237.

An important inflammatory cell type commonly found in the stroma of tumor is the tumor- associated macrophage (TAM2) Murphy JF (2014) Modulation of Angiogenesis by Tumor Associated Macrophages in the Tumor Microenvironment. MOJ Immunol 1(3): 00016.

Suggested recently to represent the 7th hallmark of cancer Hanahan D, Weinberg R.

Hallmarks of Cancer: The Next Generation. Cell.2011;144:646–674. 

By Shweta Joshi, Alok R. Singh, Lisa L.R. Hartman, Muamera Zulcic, Hyunah Ahn and Donald L. Durden DOI: 10.5772/55451

The role of TAMs in tumor growth, invasion and metastasis:

cancer cell metastasis.TAMs derived protease, such as matrix

metalloproteinases, urokinase-type plasminogen activator, and cathespin B can promote cancer cell metastasis. Murphy JF (2014) Modulation of

Angiogenesis by Tumor Associated Macrophages in the Tumor Microenvironment. MOJ Immunol 1(3): 00016.

TAMs promote cancer metastasis through several mechanisms, including

(1) promotion of angiogenesis (2) induction of tumor growth(3) enhancement of tumor cell migration and

invasion.

Tumor angiogenesisBy interacting with cancer cells, TAMs

can be induced to express more cytokines and tissue matrix-degrading enzymes, such as matrix metalloproteinases, plasminogen activators and cathepsin B, that are either direct angiogenic factors or tissue matrix modulators responsible for promoting tumor angiogenesis

TAMs and matrix degrading enzymes

TAMs produce several enzymes which can degrade the extracellular matrix (ECM). Such enzymes include several metalloproteinases (e.g., MMP-2 and MMP-9) as well as urokinase-type plasminogen activator (uPA) that degrade the ECM . Dissolution of the ECM leads to cleavages through which tumor cells can evade and metastasize. ELIAS OBEID et al. Int J Oncol. Jul 2013; 43(1): 5–12.

TAM infiltrates tumor spreading via induction of tumor angiogenesis and tumor cell invasion

Hypoxia in tumor leads to produce many factors

This factor :-differentiate blood monocytes into

macrophage TAMs and then recruited into tumor areas.

TAM respond to factors HIF-1,HIF-2 which in turn activate many genes for promoting tumor cell invasion and angiogenesis. Chun-Chung Lee et al.(2006)journal of cancer molecules.

Chun-Chung Lee et al.(2006)journal of cancer molecules.

Complex cellular interplay within the hypoxic tumor microenvironment inhibits NK-mediated killing.

Joanna Baginska et al. Front. Immunol., 25 December 2013 | doi: 10.3389/fimmu.2013.00490

Clinical association of TAM in many human cancer

Targeting monocytes and macrophages for immunotherapy of cancer.

 Monocytes (Mo) and tumor-associated

macrophages (TAMs) are promising targets for a

variety of diseases including  immunotherapy of

cancer

Targeting monocytes and macrophages for immunotherapy of cancer.

Very Much

Thank You