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Inserm, B.; Le Chapelain, O. Intratumoral Platelets. Encyclopedia. Available online: https://encyclopedia.pub/entry/22657 (accessed on 09 July 2025).
Inserm B, Le Chapelain O. Intratumoral Platelets. Encyclopedia. Available at: https://encyclopedia.pub/entry/22657. Accessed July 09, 2025.
Inserm, Benoit, Ophélie Le Chapelain. "Intratumoral Platelets" Encyclopedia, https://encyclopedia.pub/entry/22657 (accessed July 09, 2025).
Inserm, B., & Le Chapelain, O. (2022, May 06). Intratumoral Platelets. In Encyclopedia. https://encyclopedia.pub/entry/22657
Inserm, Benoit and Ophélie Le Chapelain. "Intratumoral Platelets." Encyclopedia. Web. 06 May, 2022.
Intratumoral Platelets
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This entry is adapted from the peer-reviewed paper 10.3390/cancers14092192

The tumor microenvironment (TME) has gained considerable interest because of its decisive impact on cancer progression, response to treatment, and disease recurrence. The TME can favor the proliferation, dissemination, and immune evasion of cancer cells. Likewise, there is accumulating evidence that intratumoral platelets could favor the development and aggressiveness of solid tumors, notably by influencing tumor cell phenotype and shaping the vascular and immune TME components. Yet, in contrast to other tumor-associated cell types like macrophages and fibroblasts, platelets are still often overlooked as components of the TME. This might be due, in part, to a deficit in investigating and reporting the presence of platelets in the TME and its relationships with cancer characteristics. 

platelets tumor microenvironment solid tumors

1. Introduction

The local ecosystem of tumors or tumor microenvironment (TME) has gained considerable interest because of its decisive role in maintaining a supportive niche for cancer cells. Among its numerous effects, the TME can indeed favor the proliferation, dissemination, and immune evasion of cancer cells, and can therefore impact therapy and disease recurrence. Components of the TME are highly heterogeneous and vary greatly with the cancer location, type, and stage, and can also be affected by chemotherapy [1][2]. The TME comprises an extracellular matrix, matricellular proteins, cytokines, and growth factors, as well as many different cell types, ranging from cancer cells themselves to a variety of non-malignant cells. Non-malignant cells of the TME include both nearby endogenous cells normally present in the affected tissue, such as fibroblasts and adipocytes, and cells recruited from distant sites, including immune cells and mesenchymal stem cells. Recent studies indicate that the TME also contains non-dividing supportive cells arising directly from cancer stem cells [3][4]. Tumor-associated macrophages (TAM), cancer-associated fibroblasts (CAFs), and vascular endothelial cells, together with their supporting pericytes, have been arguably among the most prominent and intensively scrutinized stromal cells of the TME [5][6][7]. Lymphocytes and adipocytes have also had their rightful share of attention [2][5][7][8]. On the contrary, although they have long been recognized to support hematogenous metastatic dissemination [9], platelets have been largely omitted from the TME equation.
Platelets are the second most numerous of the circulating blood cells. Historically known as the primary effector cells of haemostasis and thrombosis due to their ability to aggregate and promote coagulation, platelets are also recognized for their pivotal role in other processes, such as innate and adaptive immune responses [10]. Platelets are anucleated cells arising from the cytoplasmic fragmentation of megakaryocytes whose diameter of ~2–3 μm is considerably smaller than those of other circulating blood cells. Despite their small size and lack of nucleus, platelets are actually highly versatile cells whose functions far exceed the formation of blood clots. It is now well established that platelets regulate leukocyte recruitment and activation [11][12] and participate in angiogenesis [13][14][15], lymphangiogenesis [16][17][18], and tissue remodeling in general, as in wound healing [16][19][20], which all contribute to TME formation. The ability of platelets to exert such a wide range of effects is due to the fact that, in addition to their multiple receptors and interaction partners, platelets release numerous bioactive molecules stored in their secretion granules [21]. The lifespan of platelets is approximately 10 days in humans and 5 days in mice. In view of the time required for cancer to develop and spread representing years, this lifespan appears incompatible with a lengthy presence of platelets at the individual level in the tumor stroma. However, the continuous supply and renewal of platelets at a daily rate of 1011 platelets a day [22] is likely sufficient to enable a persistent presence of platelets in tumors.

2. Intratumoral Platelets: Occurrence and Possible Origins

Intriguingly, although many studies have highlighted the possible mechanisms and consequences of direct contacts and paracrine communication between platelets and cancer cells, it remains unclear if and how such interactions occur within primary tumors and their microenvironment. There is little if not no doubt that platelets and cancer cells interact closely together once cancer cells have entered the bloodstream, with the formation of tumor cell/platelet aggregates having been detected in models of experimental metastasis [23][24][25]. The lack of reports of such interactions in cancer patients can be easily explained by the scarcity of circulating tumor cells and the technical difficulties involved in detecting and isolating them [26].
In contrast to interactions in the bloodstream, evidence of interactions between platelets and cancer cells at the primary tumor site is scarcer. Yet, over the last 10 years, several experimental and clinical studies have provided data on tumor-infiltrating platelets.
In 2012, Stone et al. reported the presence of platelets in the tumor perivascular and extravascular compartments in a mouse model of ovarian cancer [27]. Further observations of intravascular, perivascular, and extravascular platelets within tumors have since been made in mouse models of colorectal and brain cancer [28][29][30]. In humans, intravascular and extravascular platelets have also been found in the stroma of various types of solid tumors, including breast, lung, pancreatic, gastric, and colorectal adenocarcinoma [31][32][33][34][35][36].
Although the studies and information on tumor-infiltrating platelets and their impact on and relation to cancer progression in humans are still limited, currently available data suggest that the presence of platelets in the tumor stroma is unlikely to be incidental. In fact, tumor-infiltrating platelets have been shown to be associated with the advanced stage of colorectal cancer [34], expression of EMT markers in pancreatic, and breast cancer [31][35], as wells as with chemoresistance and poor overall survival in breast, gastric, and pancreatic cancer [32][33][35][37]. These data, together with the observation that platelets are preferentially localized at the invasive front of pancreatic and breast tumors [31][35], suggest that, like cancer-associated thrombocytosis, the occurrence of tumor-infiltrating platelets may be indicative of an aggressive cancer phenotype.
How do platelets end up in the extravascular tumor microenvironment? One mechanism by which platelets can reach the extravascular space and interact directly with cancer cells is through the occurrence of intratumoral bleeding. Indeed, spontaneous intratumoral bleeding, related to tumor angiogenesis or to tumoral invasion, occurs in a variety of cancers [38][39][40][41][42]. Whether sporadic intratumoral bleeding events are sufficient to ensure a continuous presence of platelets in the tumor stroma is, however, uncertain. Nonetheless, even if they are spatially scattered and episodic during the course of cancer progression, platelet-cancer cell interactions subsequent to intratumoral bleeding may be sufficient to cause consequential phenotypic changes in cancer cells.
Reports of extravasated platelets found in the absence of bleeding in various inflamed organs [43], including experimental tumors [28][30][44][45], suggest that platelets may also access the extravascular tumor stroma via transmigration, either directly, or through the association with transmigrating leukocytes. The fact that platelet-specific deficiency in focal adhesion kinase [44], a protein known for its role in cell adhesion and migration, or deficiency in P-Selectin [45], a protein central to platelet-leukocyte interactions, is associated with reduced platelet deposition within the microenvironment of experimental tumors argues in favor of this possibility. However, it should be noted that, although the ability of platelets to migrate within the intravascular compartment was recently demonstrated [46][47], direct observation of active transmigration or of platelets migrating in the extravascular space has yet to be provided.
It has become clear over the last years that adaptative megakaryopoiesis programs can be triggered in inflammatory conditions [48][49]. In addition, extramedullary hematopoiesis has been shown to occur in various solid tumors [50][51][52][53][54]. Therefore, apart from blood-borne platelets, a subset of intratumoral platelets may also originate from local production programs, as suggested by the detection of megakaryocytes within the tumor stroma of patients with brain, hepatic, renal, or breast cancer [50][52][53][54].
Along with platelets infiltrating the extravascular tumor stroma, platelets interacting with the tumor vasculature likely account for a substantial fraction of intratumoral platelets. Indeed, inflammation and angiogenesis are constitutive features of solid cancers, and platelets are now known to continuously interact with and accumulate in blood vessels at sites of inflammation [46][55] and angiogenesis [13]. Furthermore, platelet accumulation in the tumor vasculature can also occur through intratumoral thrombosis [56][57][58]. Finally, circulating platelets may also interact directly with cancer cells at sites of vascular mimicry, which corresponds to areas where cancer cells organize themselves into vascular channels to supply blood independently of endothelial cells [59].

3. Shaping of the Tumor Microenvironment by Platelets

3.1. Platelets and Tumor Angiogenesis and Vascular Integrity

Studies in animal models of solid tumors strongly indicate that the functional relevance of intratumoral platelets exceeds the regulation of cancer cell phenotype, proliferation, or survival. There is converging data in favor of a role of intratumoral platelets in shaping the TME, in particular its vascular compartment. Platelets are well-known for containing a variety of angiogenic factors in their alpha granules and have been shown to participate in angiogenesis in a variety of experimental settings, including models of solid tumors [13][27][60][61][62]. The involvement of platelets in tumor angiogenesis ranges from stimulating the proliferation of endothelial cells [62][63], promoting the recruitment of pericytes [27][60][64] and that of bone marrow-derived cells [61], to maintaining tumor vessel function and integrity [60][64][65][66][67]. As a result of these activities, depletion of platelets or targeting of their activation receptors has been shown to result in reduced tumor vessel density [27][60][61], maturation [27][60][64], and functionality [56][60][64][65][66][67]. Thus, experimental studies indicate that platelets regulate tumor angiogenesis not only quantitatively but also qualitatively, notably by continuously preventing tumor vessel leakage and bleeding [60][64][65][66][67]. The latter supportive functions of platelets towards tumor vessel integrity emphasize the importance of the physical presence of platelets within tumors for regulating the TME. Indeed, the stabilization of both angiogenic and inflamed vessels by platelets requires direct contacts between platelets and such vessels [13][55]. Interestingly, several studies in mouse models of solid cancers are converging to suggest that targeting the vasculoprotective function of platelets in tumors can enhance the intratumor delivery and antitumor effects of chemotherapeutic drugs such as paclitaxel via the induction of tumor vascular leakiness [65][68][69].
Despite evidence from experimental models, if and how tumor platelet content correlates with tumor angiogenesis in cancer patients has not been investigated. Additionally, it is worth mentioning that platelet depletion had no impact on tumor vessel density in a mouse model of glioblastoma [63], which suggests that the contribution of platelets to tumor angiogenesis may vary with the cancer type.

3.2. Platelets and Tumor Lymphangiogenesis

Platelets are now well-established actors of lymphangiogenesis. They ensure proper separation of blood and lymphatic vessels during development, notably by regulating the proliferation, migration, and tube formation of lymphatic endothelial cells (LECs) through engagement of their CLEC-2 receptor by podoplanin on LECs [17][70]. Platelet CLEC-2 is also required for the development and maintenance of lymph nodes [71]. Remarkably, platelets are not required for maintaining the mature blood and lymphatic systems separated in the absence of challenges post-development [72]. However, recent studies in mice have indicated that, upon vascular remodeling, such as during wound-healing or in the TME, platelets again intervene in lymphangiogenesis by stimulating lymphatic growth via the secretion of VEGF-C [16] and by preventing the mixing of lymphatic and blood circulations through the engagement of CLEC-2 [72]. Considering that lymphatics provide routes for the dissemination of cancer cells, these data suggest that platelets may promote metastasis not only via their direct interactions with cancer cells but also through shaping the TME and giving cancer cells access to regional lymph nodes. The description of a positive correlation between intratumoral platelet content and both lymphatic vessel density and lymphovascular invasion in human esophageal cancer supports this hypothesis [70].

3.3. Platelets and the Tumor Immune Microenvironment

In addition to their role in tumor blood and lymphatic network formation, platelets may potentially also participate in setting up the immune component of the TME. Platelets indeed regulate the infiltration and functions of leukocytes in many inflammatory diseases and conditions [12][73]. Furthermore, platelets were found to recruit neutrophils to form early metastatic niches in the lungs of mice injected intravenously with various types of tumor cells [74]. Intriguingly, however, there are very few reports linking platelets to tumor immune cell content. Among the sparse available data, induction of acute thrombocytopenia was shown to have no significant impact on neutrophil and macrophage infiltration into the stroma of subcutaneously implanted Lewis lung carcinoma tumors in mice [67]. In contrast to these results, there is evidence supporting the role of platelets in controlling intratumor T cell infiltration. As mentioned above, functional PD-L1 was found on platelets of patients with PD-L1-positive lung cancers [75]. Interestingly, high levels of PD-L1 on platelets were associated with lower numbers of infiltrating T cells in the TME [75]. In agreement with these results, in mice, platelet depletion caused an increase in T cells in the TME of a colon adenocarcinoma model, an effect that could be reverted by transfusion of PD-L1-positive but not PD-L1-negative platelets [76]. Thus, together, these clinical and experimental results suggest a possible role of platelet PD-L1 in tumor immune evasion [76].
Finally, the observation of platelets interacting with podoplanin-expressing CAF in pancreatic cancer [77] or in peritoneal metastasis of gastric cancer [78], suggests that platelets may influence the activities of other major actors of the TME.

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Subjects: Pathology
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benoit INSERM
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Ophélie LE CHAPELAIN
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Update Date: 07 May 2022
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